210 results on '"A, Sesso"'
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2. Whole-genome sequencing reveals host factors underlying critical COVID-19
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Kousathanas, A, Pairo-Castineira, E, Rawlik, K, Stuckey, A, Odhams, C, Walker, S, Russell, C, Malinauskas, T, Wu, Y, Millar, J, Shen, X, Elliott, K, Griffiths, F, Oosthuyzen, W, Morrice, K, Keating, S, Wang, B, Rhodes, D, Klaric, L, Zechner, M, Parkinson, N, Siddiq, A, Goddard, P, Donovan, S, Maslove, D, Nichol, A, Semple, M, Zainy, T, Maleady-Crowe, F, Todd, L, Salehi, S, Knight, J, Elgar, G, Chan, G, Arumugam, P, Patch, C, Rendon, A, Bentley, D, Kingsley, C, Kosmicki, J, Horowitz, J, Baras, A, Abecasis, G, Ferreira, M, Justice, A, Mirshahi, T, Oetjens, M, Rader, D, Ritchie, M, Verma, A, Fowler, T, Shankar-Hari, M, Summers, C, Hinds, C, Horby, P, Ling, L, Mcauley, D, Montgomery, H, Openshaw, P, Elliott, P, Walsh, T, Tenesa, A, Shelton, J, Shastri, A, Ye, C, Weldon, C, Filshtein-Sonmez, T, Coker, D, Symons, A, Esparza-Gordillo, J, Aslibekyan, S, Auton, A, Pathak, G, Karjalainen, J, Stevens, C, Andrews, S, Kanai, M, Cordioli, M, Polimanti, R, Pirinen, M, Harerimana, N, Veerapen, K, Wolford, B, Nguyen, H, Solomonson, M, Liao, R, Chwialkowska, K, Trankiem, A, Balaconis, M, Hayward, C, Richmond, A, Campbell, A, Morris, M, Fawns-Ritchie, C, Glessner, J, Shaw, D, Chang, X, Polikowski, H, Petty, L, Chen, H, Wanying, Z, Hakonarson, H, Porteous, D, Below, J, North, K, Mccormick, J, Timmers, P, Wilson, J, D'Mellow, K, Kerr, S, Niemi, M, Nkambul, L, von Hohenstaufen, K, Sobh, A, Eltoukhy, M, Yassen, A, Hegazy, M, Okasha, K, Eid, M, Moahmed, H, Shahin, D, El-Sherbiny, Y, Elhadidy, T, Abd Elghafar, M, El-Jawhari, J, Mohamed, A, Elnagdy, M, Samir, A, Abdel-Aziz, M, Khafaga, W, El-Lawaty, W, Torky, M, El-shanshory, M, Batini, C, Lee, P, Shrine, N, Williams, A, Tobin, M, Guyatt, A, John, C, Packer, R, Ali, A, Free, R, Wang, X, Wain, L, Hollox, E, Venn, L, Bee, C, Adams, E, Niavarani, A, Sharififard, B, Aliannejad, R, Amirsavadkouhi, A, Naderpour, Z, Tadi, H, Aleagha, A, Ahmadi, S, Moghaddam, S, Adamsara, A, Saeedi, M, Abdollahi, H, Hosseini, A, Chariyavilaskul, P, Chamnanphon, M, Suttichet, T, Shotelersuk, V, Pongpanich, M, Phokaew, C, Chetruengchai, W, Jantarabenjakul, W, Putchareon, O, Torvorapanit, P, Puthanakit, T, Suchartlikitwong, P, Hirankarn, N, Nilaratanakul, V, Sodsai, P, Brumpton, B, Hveem, K, Willer, C, Zhou, W, Rogne, T, Solligard, E, Asvold, B, Abedalthagafi, M, Alaamery, M, Alqahtani, S, Barakeh, D, Al Harthi, F, Alsolm, E, Safieh, L, Alowayn, A, Alqubaishi, F, Al Mutairi, A, Mangul, S, Alshareef, A, Sawaji, M, Almutairi, M, Aljawini, N, Albesher, N, Arabi, Y, Mahmoud, E, Khattab, A, Halawani, R, Alahmadey, Z, Albakri, J, Felemban, W, Suliman, B, Hasanato, R, Al-Awdah, L, Alghamdi, J, Alzahrani, D, Aljohani, S, Al-Afghani, H, Alrashed, M, Aldhawi, N, Albardis, H, Alkwai, S, Alswailm, M, Almalki, F, Albeladi, M, Almohammed, I, Barhoush, E, Albader, A, Massadeh, S, Almalik, A, Alotaibi, S, Alghamdi, B, Jung, J, Fawzy, M, Lee, Y, Magnus, P, Trogstad, L, Helgeland, O, Harris, J, Mangino, M, Spector, T, Duncan, E, Smieszek, S, Przychodzen, B, Polymeropoulos, C, Polymeropoulos, V, Polymeropoulos, M, Fernandez-Cadenas, I, Perez-Tur, J, Llucia-Carol, L, Cullell, N, Muino, E, Carcel-Marquez, J, Dediego, M, Iglesias, L, Planas, A, Soriano, A, Rico, V, Aguero, D, Bedini, J, Lozano, F, Domingo, C, Robles, V, Ruiz-Jaen, F, Marquez, L, Gomez, J, Coto, E, Albaiceta, G, Garcia-Clemente, M, Dalmau, D, Arranz, M, Dietl, B, Serra-Llovich, A, Soler, P, Colobran, R, Martin-Nalda, A, Martinez, A, Bernardo, D, Rojo, S, Fiz-Lopez, A, Arribas, E, de la Cal-Sabater, P, Segura, T, Gonzalez-Villa, E, Serrano-Heras, G, Marti-Fabregas, J, Jimenez-Xarrie, E, de Felipe Mimbrera, A, Masjuan, J, Garcia-Madrona, S, Dominguez-Mayoral, A, Villalonga, J, Menendez-Valladares, P, Chasman, D, Buring, J, Ridker, P, Franco, G, Sesso, H, Manson, J, Medina-Gomez, C, Uitterlinden, A, Ikram, M, Kristiansson, K, Koskelainen, S, Perola, M, Donner, K, Kivinen, K, Palotie, A, Ripatti, S, Ruotsalainen, S, Kaunisto, M, Nakanishi, T, Butler-Laporte, G, Forgetta, V, Morrison, D, Ghosh, B, Laurent, L, Belisle, A, Henry, D, Abdullah, T, Adeleye, O, Mamlouk, N, Kimchi, N, Afrasiabi, Z, Rezk, N, Vulesevic, B, Bouab, M, Guzman, C, Petitjean, L, Tselios, C, Xue, X, Schurr, E, Afilalo, J, Afilalo, M, Oliveira, M, Brenner, B, Lepage, P, Ragoussis, J, Auld, D, Brassard, N, Durand, M, Chasse, M, Kaufmann, D, Lathrop, G, Mooser, V, Richards, J, Li, R, Adra, D, Rahmouni, S, Georges, M, Moutschen, M, Misset, B, Darcis, G, Guiot, J, Guntz, J, Azarzar, S, Gofflot, S, Beguin, Y, Claassen, S, Malaise, O, Huynen, P, Meuris, C, Thys, M, Jacques, J, Leonard, P, Frippiat, F, Giot, J, Sauvage, A, von Frenckell, C, Belhaj, Y, Lambermont, B, Pigazzini, S, Nkambule, L, Daya, M, Shortt, J, Rafaels, N, Wicks, S, Crooks, K, Barnes, K, Gignoux, C, Chavan, S, Laisk, T, Lall, K, Lepamets, M, Magi, R, Esko, T, Reimann, E, Milani, L, Alavere, H, Metsalu, K, Puusepp, M, Metspalu, A, Naaber, P, Laane, E, Pesukova, J, Peterson, P, Kisand, K, Tabri, J, Allos, R, Hensen, K, Starkopf, J, Ringmets, I, Tamm, A, Kallaste, A, Bochud, P, Rivolta, C, Bibert, S, Quinodoz, M, Kamdar, D, Boillat, N, Nussle, S, Albrich, W, Suh, N, Neofytos, D, Erard, V, Voide, C, de Cid, R, Galvan-Femenia, I, Blay, N, Carreras, A, Cortes, B, Farre, X, Sumoy, L, Moreno, V, Mercader, J, Guindo-Martinez, M, Torrents, D, Kogevinas, M, Garcia-Aymerich, J, Castano-Vinyals, G, Dobano, C, Renieri, A, Mari, F, Fallerini, C, Daga, S, Benetti, E, Baldassarri, M, Fava, F, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Beligni, G, Tommasi, A, Di Sarno, L, Palmieri, M, Carriero, M, Alaverdian, D, Busani, S, Bruno, R, Vecchia, M, Belli, M, Picchiotti, N, Sanarico, M, Gori, M, Furini, S, Mantovani, S, Ludovisi, S, Mondelli, M, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Vaghi, M, Rusconi, S, Siano, M, Montagnani, F, Emiliozzi, A, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Bandini, M, Caldarelli, G, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazzi, A, Lorubbio, M, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Cossarizza, A, Antinori, A, Vergori, A, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Gabbi, C, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, La Rovere, M, Sarzi-Braga, S, Bussotti, M, Ceri, S, Pinoli, P, Raimondi, F, Biscarini, F, Stella, A, Zguro, K, Capitani, K, Suardi, C, Dei, S, Parati, G, Ravaglia, S, Artuso, R, Botta, G, Di Domenico, P, Rancan, I, Perrella, A, Bianchi, F, Romani, D, Bergomi, P, Catena, E, Colombo, R, Tanfoni, M, Vincenti, A, Ferri, C, Grassi, D, Pessina, G, Tumbarello, M, Di Pietro, M, Sabrina, R, Luchi, S, Barbieri, C, Acquilini, D, Andreucci, E, Segala, F, Tiseo, G, Falcone, M, Lista, M, Poscente, M, De Vivo, O, Petrocelli, P, Guarnaccia, A, Baroni, S, Smith, A, Boughton, A, Li, K, Lefaive, J, Annis, A, Chittoor, G, Josyula, N, Leader, J, Carey, D, Gass, M, Cantor, M, Yadav, A, van Heel, D, Hunt, K, Mason, D, Huang, Q, Finer, S, Trivedi, B, Griffiths, C, Martin, H, Wright, J, Trembath, R, Soranzo, N, Zhao, J, Butterworth, A, Danesh, J, Di Angelantonio, E, Franke, L, Boezen, M, Deelen, P, Claringbould, A, Lopera, E, Warmerdam, R, Vonk, J, van Blokland, I, Lanting, P, Ori, A, Zollner, S, Wang, J, Beck, A, Peloso, G, Ho, Y, Sun, Y, Huffman, J, O'Donnell, C, Cho, K, Tsao, P, Gaziano, J, Nivard, M, de Geus, E, Bartels, M, Jan Hottenga, J, Weiss, S, Karlson, E, Smoller, J, Green, R, Feng, Y, Murphy, S, Meigs, J, Woolley, A, Perez, E, Li, B, Verma, S, Lucas, A, Bradford, Y, Zeberg, H, Frithiof, R, Hultstrom, M, Lipcsey, M, Tardif, N, Rooyackers, O, Grip, J, Maricic, T, Karczewski, K, Atkinson, E, Tsuo, K, Baya, N, Turley, P, Gupta, R, Callier, S, Walters, R, Palmer, D, Sarma, G, Cheng, N, Lu, W, Bryant, S, Churchhouse, C, Cusick, C, Goldstein, J, King, D, Seed, C, Finucane, H, Martin, A, Satterstrom, F, Wilson, D, Armstrong, J, Rudkin, J, Band, G, Earle, S, Lin, S, Arning, N, Crook, D, Wyllie, D, O'Connell, A, Spencer, C, Koelling, N, Caulfield, M, Scott, R, Moutsianas, L, Pasko, D, Ball, C, Hong, E, Rand, K, Girshick, A, Guturu, H, Baltzell, A, Roberts, G, Park, D, Coignet, M, Mccurdy, S, Knight, S, Partha, R, Rhead, B, Zhang, M, Berkowitz, N, Gaddis, M, Noto, K, Ruiz, L, Pavlovic, M, Sloofman, L, Charney, A, Beckmann, N, Schadt, E, Jordan, D, Thompson, R, Gettler, K, Abul-Husn, N, Ascolillo, S, Buxbaum, J, Chaudhary, K, Cho, J, Itan, Y, Kenny, E, Belbin, G, Sealfon, S, Sebra, R, Salib, I, Collins, B, Levy, T, Britvan, B, Keller, K, Tang, L, Peruggia, M, Hiester, L, Niblo, K, Aksentijevich, A, Labkowsky, A, Karp, A, Zlatopolsky, M, Preuss, M, Loos, R, Nadkarni, G, Do, R, Hoggart, C, Choi, S, Underwood, S, O'Reilly, P, Huckins, L, Zyndorf, M, Daly, M, Neale, B, Ganna, A, Fawkes, A, Murphy, L, Rowan, K, Ponting, C, Vitart, V, Yang, J, Bretherick, A, Hendry, S, Law, A, Baillie, J, Kousathanas A., Pairo-Castineira E., Rawlik K., Stuckey A., Odhams C. A., Walker S., Russell C. D., Malinauskas T., Wu Y., Millar J., Shen X., Elliott K. S., Griffiths F., Oosthuyzen W., Morrice K., Keating S., Wang B., Rhodes D., Klaric L., Zechner M., Parkinson N., Siddiq A., Goddard P., Donovan S., Maslove D., Nichol A., Semple M. G., Zainy T., Maleady-Crowe F., Todd L., Salehi S., Knight J., Elgar G., Chan G., Arumugam P., Patch C., Rendon A., Bentley D., Kingsley C., Kosmicki J. A., Horowitz J. E., Baras A., Abecasis G. R., Ferreira M. A. R., Justice A., Mirshahi T., Oetjens M., Rader D. J., Ritchie M. D., Verma A., Fowler T. A., Shankar-Hari M., Summers C., Hinds C., Horby P., Ling L., McAuley D., Montgomery H., Openshaw P. J. M., Elliott P., Walsh T., Tenesa A., Shelton J. F., Shastri A. J., Ye C., Weldon C. H., Filshtein-Sonmez T., Coker D., Symons A., Esparza-Gordillo J., Aslibekyan S., Auton A., Pathak G. A., Karjalainen J., Stevens C., Andrews S. J., Kanai M., Cordioli M., Polimanti R., Pirinen M., Harerimana N., Veerapen K., Wolford B., Nguyen H., Solomonson M., Liao R. G., Chwialkowska K., Trankiem A., Balaconis M. K., Hayward C., Richmond A., Campbell A., Morris M., Fawns-Ritchie C., Glessner J. T., Shaw D. M., Chang X., Polikowski H., Petty L. E., Chen H. -H., Wanying Z., Hakonarson H., Porteous D. J., Below J., North K., McCormick J. B., Timmers P. R. H. J., Wilson J. F., D'Mellow K., Kerr S. M., Niemi M. E. K., Nkambul L., von Hohenstaufen K. A., Sobh A., Eltoukhy M. M., Yassen A. M., Hegazy M. A. F., Okasha K., Eid M. A., Moahmed H. S., Shahin D., El-Sherbiny Y. M., Elhadidy T. A., Abd Elghafar M. S., El-Jawhari J. J., Mohamed A. A. S., Elnagdy M. H., Samir A., Abdel-Aziz M., Khafaga W. T., El-Lawaty W. M., Torky M. S., El-shanshory M. R., Batini C., Lee P. H., Shrine N., Williams A. T., Tobin M. D., Guyatt A. L., John C., Packer R. J., Ali A., Free R. C., Wang X., Wain L. V., Hollox E. J., Venn L. D., Bee C. E., Adams E. L., Niavarani A., Sharififard B., Aliannejad R., Amirsavadkouhi A., Naderpour Z., Tadi H. A., Aleagha A. E., Ahmadi S., Moghaddam S. B. M., Adamsara A., Saeedi M., Abdollahi H., Hosseini A., Chariyavilaskul P., Chamnanphon M., Suttichet T. B., Shotelersuk V., Pongpanich M., Phokaew C., Chetruengchai W., Jantarabenjakul W., Putchareon O., Torvorapanit P., Puthanakit T., Suchartlikitwong P., Hirankarn N., Nilaratanakul V., Sodsai P., Brumpton B. M., Hveem K., Willer C., Zhou W., Rogne T., Solligard E., Asvold B. O., Abedalthagafi M., Alaamery M., Alqahtani S., Barakeh D., Al Harthi F., Alsolm E., Safieh L. A., Alowayn A. M., Alqubaishi F., Al Mutairi A., Mangul S., Alshareef A., Sawaji M., Almutairi M., Aljawini N., Albesher N., Arabi Y. M., Mahmoud E. S., Khattab A. K., Halawani R. T., Alahmadey Z. Z., Albakri J. K., Felemban W. A., Suliman B. A., Hasanato R., Al-Awdah L., Alghamdi J., AlZahrani D., AlJohani S., Al-Afghani H., Alrashed M., AlDhawi N., AlBardis H., Alkwai S., Alswailm M., Almalki F., Albeladi M., Almohammed I., Barhoush E., Albader A., Massadeh S., AlMalik A., Alotaibi S., Alghamdi B., Jung J., Fawzy M. S., Lee Y., Magnus P., Trogstad L. -I. S., Helgeland O., Harris J. R., Mangino M., Spector T. D., Duncan E., Smieszek S. P., Przychodzen B. P., Polymeropoulos C., Polymeropoulos V., Polymeropoulos M. H., Fernandez-Cadenas I., Perez-Tur J., Llucia-Carol L., Cullell N., Muino E., Carcel-Marquez J., DeDiego M. L., Iglesias L. L., Planas A. M., Soriano A., Rico V., Aguero D., Bedini J. L., Lozano F., Domingo C., Robles V., Ruiz-Jaen F., Marquez L., Gomez J., Coto E., Albaiceta G. M., Garcia-Clemente M., Dalmau D., Arranz M. J., Dietl B., Serra-Llovich A., Soler P., Colobran R., Martin-Nalda A., Martinez A. P., Bernardo D., Rojo S., Fiz-Lopez A., Arribas E., de la Cal-Sabater P., Segura T., Gonzalez-Villa E., Serrano-Heras G., Marti-Fabregas J., Jimenez-Xarrie E., de Felipe Mimbrera A., Masjuan J., Garcia-Madrona S., Dominguez-Mayoral A., Villalonga J. M., Menendez-Valladares P., Chasman D. I., Buring J. E., Ridker P. M., Franco G., Sesso H. D., Manson J. A. E., Glessner J. R., Medina-Gomez C., Uitterlinden A. G., Ikram M. A., Kristiansson K., Koskelainen S., Perola M., Donner K., Kivinen K., Palotie A., Ripatti S., Ruotsalainen S., Kaunisto M., Nakanishi T., Butler-Laporte G., Forgetta V., Morrison D. R., Ghosh B., Laurent L., Belisle A., Henry D., Abdullah T., Adeleye O., Mamlouk N., Kimchi N., Afrasiabi Z., Rezk N., Vulesevic B., Bouab M., Guzman C., Petitjean L., Tselios C., Xue X., Schurr E., Afilalo J., Afilalo M., Oliveira M., Brenner B., Lepage P., Ragoussis J., Auld D., Brassard N., Durand M., Chasse M., Kaufmann D. E., Lathrop G. M., Mooser V., Richards J. B., Li R., Adra D., Rahmouni S., Georges M., Moutschen M., Misset B., Darcis G., Guiot J., Guntz J., Azarzar S., Gofflot S., Beguin Y., Claassen S., Malaise O., Huynen P., Meuris C., Thys M., Jacques J., Leonard P., Frippiat F., Giot J. -B., Sauvage A. -S., von Frenckell C., Belhaj Y., Lambermont B., Pigazzini S., Nkambule L., Daya M., Shortt J., Rafaels N., Wicks S. J., Crooks K., Barnes K. C., Gignoux C. R., Chavan S., Laisk T., Lall K., Lepamets M., Magi R., Esko T., Reimann E., Milani L., Alavere H., Metsalu K., Puusepp M., Metspalu A., Naaber P., Laane E., Pesukova J., Peterson P., Kisand K., Tabri J., Allos R., Hensen K., Starkopf J., Ringmets I., Tamm A., Kallaste A., Bochud P. -Y., Rivolta C., Bibert S., Quinodoz M., Kamdar D., Boillat N., Nussle S. G., Albrich W., Suh N., Neofytos D., Erard V., Voide C., de Cid R., Galvan-Femenia I., Blay N., Carreras A., Cortes B., Farre X., Sumoy L., Moreno V., Mercader J. M., Guindo-Martinez M., Torrents D., Kogevinas M., Garcia-Aymerich J., Castano-Vinyals G., Dobano C., Renieri A., Mari F., Fallerini C., Daga S., Benetti E., Baldassarri M., Fava F., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Beligni G., Tommasi A., Di Sarno L., Palmieri M., Carriero M. L., Alaverdian D., Busani S., Bruno R., Vecchia M., Belli M. A., Picchiotti N., Sanarico M., Gori M., Furini S., Mantovani S., Ludovisi S., Mondelli M. U., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Vaghi M., Rusconi S., Siano M., Montagnani F., Emiliozzi A., Fabbiani M., Rossetti B., Bargagli E., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Bandini M., Caldarelli G. P., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Pancrazzi A., Lorubbio M., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Cossarizza A., Antinori A., Vergori A., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Gabbi C., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., La Rovere M. T., Sarzi-Braga S., Bussotti M., Ceri S., Pinoli P., Raimondi F., Biscarini F., Stella A., Zguro K., Capitani K., Suardi C., Dei S., Parati G., Ravaglia S., Artuso R., Botta G., Di Domenico P., Rancan I., Perrella A., Bianchi F., Romani D., Bergomi P., Catena E., Colombo R., Tanfoni M., Vincenti A., Ferri C., Grassi D., Pessina G., Tumbarello M., Di Pietro M., Sabrina R., Luchi S., Barbieri C., Acquilini D., Andreucci E., Segala F. V., Tiseo G., Falcone M., Lista M., Poscente M., De Vivo O., Petrocelli P., Guarnaccia A., Baroni S., Smith A. V., Boughton A. P., Li K. W., LeFaive J., Annis A., Justice A. E., Chittoor G., Josyula N. S., Leader J. B., Carey D. J., Gass M. C., Cantor M. N., Yadav A., van Heel D. A., Hunt K. A., Mason D., Huang Q. Q., Finer S., Trivedi B., Griffiths C. J., Martin H. C., Wright J., Trembath R. C., Soranzo N., Zhao J. 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A., Hasanato R., Al-Awdah L., Alghamdi J., AlZahrani D., AlJohani S., Al-Afghani H., Alrashed M., AlDhawi N., AlBardis H., Alkwai S., Alswailm M., Almalki F., Albeladi M., Almohammed I., Barhoush E., Albader A., Massadeh S., AlMalik A., Alotaibi S., Alghamdi B., Jung J., Fawzy M. S., Lee Y., Magnus P., Trogstad L. -I. S., Helgeland O., Harris J. R., Mangino M., Spector T. D., Duncan E., Smieszek S. P., Przychodzen B. P., Polymeropoulos C., Polymeropoulos V., Polymeropoulos M. H., Fernandez-Cadenas I., Perez-Tur J., Llucia-Carol L., Cullell N., Muino E., Carcel-Marquez J., DeDiego M. L., Iglesias L. L., Planas A. M., Soriano A., Rico V., Aguero D., Bedini J. L., Lozano F., Domingo C., Robles V., Ruiz-Jaen F., Marquez L., Gomez J., Coto E., Albaiceta G. M., Garcia-Clemente M., Dalmau D., Arranz M. J., Dietl B., Serra-Llovich A., Soler P., Colobran R., Martin-Nalda A., Martinez A. P., Bernardo D., Rojo S., Fiz-Lopez A., Arribas E., de la Cal-Sabater P., Segura T., Gonzalez-Villa E., Serrano-Heras G., Marti-Fabregas J., Jimenez-Xarrie E., de Felipe Mimbrera A., Masjuan J., Garcia-Madrona S., Dominguez-Mayoral A., Villalonga J. M., Menendez-Valladares P., Chasman D. I., Buring J. E., Ridker P. M., Franco G., Sesso H. D., Manson J. A. E., Glessner J. R., Medina-Gomez C., Uitterlinden A. G., Ikram M. A., Kristiansson K., Koskelainen S., Perola M., Donner K., Kivinen K., Palotie A., Ripatti S., Ruotsalainen S., Kaunisto M., Nakanishi T., Butler-Laporte G., Forgetta V., Morrison D. R., Ghosh B., Laurent L., Belisle A., Henry D., Abdullah T., Adeleye O., Mamlouk N., Kimchi N., Afrasiabi Z., Rezk N., Vulesevic B., Bouab M., Guzman C., Petitjean L., Tselios C., Xue X., Schurr E., Afilalo J., Afilalo M., Oliveira M., Brenner B., Lepage P., Ragoussis J., Auld D., Brassard N., Durand M., Chasse M., Kaufmann D. E., Lathrop G. M., Mooser V., Richards J. B., Li R., Adra D., Rahmouni S., Georges M., Moutschen M., Misset B., Darcis G., Guiot J., Guntz J., Azarzar S., Gofflot S., Beguin Y., Claassen S., Malaise O., Huynen P., Meuris C., Thys M., Jacques J., Leonard P., Frippiat F., Giot J. -B., Sauvage A. -S., von Frenckell C., Belhaj Y., Lambermont B., Pigazzini S., Nkambule L., Daya M., Shortt J., Rafaels N., Wicks S. J., Crooks K., Barnes K. C., Gignoux C. R., Chavan S., Laisk T., Lall K., Lepamets M., Magi R., Esko T., Reimann E., Milani L., Alavere H., Metsalu K., Puusepp M., Metspalu A., Naaber P., Laane E., Pesukova J., Peterson P., Kisand K., Tabri J., Allos R., Hensen K., Starkopf J., Ringmets I., Tamm A., Kallaste A., Bochud P. -Y., Rivolta C., Bibert S., Quinodoz M., Kamdar D., Boillat N., Nussle S. G., Albrich W., Suh N., Neofytos D., Erard V., Voide C., de Cid R., Galvan-Femenia I., Blay N., Carreras A., Cortes B., Farre X., Sumoy L., Moreno V., Mercader J. M., Guindo-Martinez M., Torrents D., Kogevinas M., Garcia-Aymerich J., Castano-Vinyals G., Dobano C., Renieri A., Mari F., Fallerini C., Daga S., Benetti E., Baldassarri M., Fava F., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Beligni G., Tommasi A., Di Sarno L., Palmieri M., Carriero M. L., Alaverdian D., Busani S., Bruno R., Vecchia M., Belli M. A., Picchiotti N., Sanarico M., Gori M., Furini S., Mantovani S., Ludovisi S., Mondelli M. U., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Vaghi M., Rusconi S., Siano M., Montagnani F., Emiliozzi A., Fabbiani M., Rossetti B., Bargagli E., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Bandini M., Caldarelli G. P., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Pancrazzi A., Lorubbio M., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Cossarizza A., Antinori A., Vergori A., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Gabbi C., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., La Rovere M. T., Sarzi-Braga S., Bussotti M., Ceri S., Pinoli P., Raimondi F., Biscarini F., Stella A., Zguro K., Capitani K., Suardi C., Dei S., Parati G., Ravaglia S., Artuso R., Botta G., Di Domenico P., Rancan I., Perrella A., Bianchi F., Romani D., Bergomi P., Catena E., Colombo R., Tanfoni M., Vincenti A., Ferri C., Grassi D., Pessina G., Tumbarello M., Di Pietro M., Sabrina R., Luchi S., Barbieri C., Acquilini D., Andreucci E., Segala F. V., Tiseo G., Falcone M., Lista M., Poscente M., De Vivo O., Petrocelli P., Guarnaccia A., Baroni S., Smith A. V., Boughton A. P., Li K. W., LeFaive J., Annis A., Justice A. E., Chittoor G., Josyula N. S., Leader J. B., Carey D. J., Gass M. C., Cantor M. N., Yadav A., van Heel D. A., Hunt K. A., Mason D., Huang Q. Q., Finer S., Trivedi B., Griffiths C. J., Martin H. C., Wright J., Trembath R. C., Soranzo N., Zhao J. H., Butterworth A. S., Danesh J., Di Angelantonio E., Franke L., Boezen M., Deelen P., Claringbould A., Lopera E., Warmerdam R., Vonk J. M., van Blokland I., Lanting P., Ori A. P. S., Zollner S., Wang J., Beck A., Peloso G., Ho Y. -L., Sun Y. V., Huffman J. E., O'Donnell C. J., Cho K., Tsao P., Gaziano J. M., Nivard M., de Geus E., Bartels M., Jan Hottenga J., Weiss S. T., Karlson E. W., Smoller J. W., Green R. C., Feng Y. -C. A., Mercader J., Murphy S. N., Meigs J. B., Woolley A. E., Perez E. F., Rader D., Li B., Verma S. S., Lucas A., Bradford Y., Zeberg H., Frithiof R., Hultstrom M., Lipcsey M., Tardif N., Rooyackers O., Grip J., Maricic T., Karczewski K. J., Atkinson E. G., Tsuo K., Baya N., Turley P., Gupta R., Callier S., Walters R. K., Palmer D. S., Sarma G., Cheng N., Lu W., Bryant S., Churchhouse C., Cusick C., Goldstein J. I., King D., Seed C., Finucane H., Martin A. R., Satterstrom F. K., Wilson D. J., Armstrong J., Rudkin J. K., Band G., Earle S. G., Lin S. -K., Arning N., Crook D. W., Wyllie D. H., O'Connell A. M., Spencer C. C. A., Koelling N., Caulfield M. J., Scott R. H., Fowler T., Moutsianas L., Pasko D., Ball C. A., Hong E. L., Rand K., Girshick A., Guturu H., Baltzell A. H., Roberts G., Park D., Coignet M., McCurdy S., Knight S., Partha R., Rhead B., Zhang M., Berkowitz N., Gaddis M., Noto K., Ruiz L., Pavlovic M., Sloofman L. G., Charney A. W., Beckmann N. D., Schadt E. E., Jordan D. M., Thompson R. C., Gettler K., Abul-Husn N. S., Ascolillo S., Buxbaum J. D., Chaudhary K., Cho J. H., Itan Y., Kenny E. E., Belbin G. M., Sealfon S. C., Sebra R. P., Salib I., Collins B. L., Levy T., Britvan B., Keller K., Tang L., Peruggia M., Hiester L. L., Niblo K., Aksentijevich A., Labkowsky A., Karp A., Zlatopolsky M., Preuss M., Loos R. J. F., Nadkarni G. N., Do R., Hoggart C., Choi S., Underwood S. J., O'Reilly P., Huckins L. M., Zyndorf M., Daly M. J., Neale B. M., Ganna A., Fawkes A., Murphy L., Rowan K., Ponting C. P., Vitart V., Yang J., Bretherick A. D., Hendry S. C., Law A., and Baillie J. K.
- Abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
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- 2022
3. The blood proteome of imminent lung cancer diagnosis
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Albanes, D, Alcala, K, Alcala, N, Amos, C, Arslan, AA, Bassett, JK, Brennan, P, Cai, Q, Chen, C, Feng, X, Freedman, ND, Guida, F, Hung, RJ, Hveem, K, Johansson, M, Koh, W-P, Langhammer, A, Milne, RL, Muller, D, Onwuka, J, Sorgjerd, EP, Robbins, HA, Sesso, HD, Severi, G, Shu, X-O, Sieri, S, Smith-Byrne, K, Stevens, V, Tinker, L, Tjonneland, A, Visvanathan, K, Wang, Y, Wang, R, Weinstein, S, Yuan, J-M, Zahed, H, Zhang, X, Zheng, W, Albanes, D, Alcala, K, Alcala, N, Amos, C, Arslan, AA, Bassett, JK, Brennan, P, Cai, Q, Chen, C, Feng, X, Freedman, ND, Guida, F, Hung, RJ, Hveem, K, Johansson, M, Koh, W-P, Langhammer, A, Milne, RL, Muller, D, Onwuka, J, Sorgjerd, EP, Robbins, HA, Sesso, HD, Severi, G, Shu, X-O, Sieri, S, Smith-Byrne, K, Stevens, V, Tinker, L, Tjonneland, A, Visvanathan, K, Wang, Y, Wang, R, Weinstein, S, Yuan, J-M, Zahed, H, Zhang, X, and Zheng, W
- Abstract
Identification of risk biomarkers may enhance early detection of smoking-related lung cancer. We measured between 392 and 1,162 proteins in blood samples drawn at most three years before diagnosis in 731 smoking-matched case-control sets nested within six prospective cohorts from the US, Europe, Singapore, and Australia. We identify 36 proteins with independently reproducible associations with risk of imminent lung cancer diagnosis (all p < 4 × 10-5). These include a few markers (e.g. CA-125/MUC-16 and CEACAM5/CEA) that have previously been reported in studies using pre-diagnostic blood samples for lung cancer. The 36 proteins include several growth factors (e.g. HGF, IGFBP-1, IGFP-2), tumor necrosis factor-receptors (e.g. TNFRSF6B, TNFRSF13B), and chemokines and cytokines (e.g. CXL17, GDF-15, SCF). The odds ratio per standard deviation range from 1.31 for IGFBP-1 (95% CI: 1.17-1.47) to 2.43 for CEACAM5 (95% CI: 2.04-2.89). We map the 36 proteins to the hallmarks of cancer and find that activation of invasion and metastasis, proliferative signaling, tumor-promoting inflammation, and angiogenesis are most frequently implicated.
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- 2023
4. Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program
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Robbins, Hilary A., Alcala, Karine, Moez, Elham Khodayari, Guida, Florence, Thomas, Sera, Zahed, Hana, Warkentin, Matthew T., Smith-Byrne, Karl, Brhane, Yonathan, Muller, David, Feng, Xiaoshuang, Albanes, Demetrius, Aldrich, Melinda C., Arslan, Alan A., Bassett, Julie, Berg, Christine D., Cai, Qiuyin, Chen, Chu, Davies, Michael P.A., Diergaarde, Brenda, Field, John K., Freedman, Neal D., Huang, Wen-Yi, Johansson, Mikael, Jones, Michael, Koh, Woon-Puay, Lam, Stephen, Lan, Qing, Langhammer, Arnulf, Liao, Linda M., Liu, Geoffrey, Malekzadeh, Reza, Milne, Roger L., Montuenga, Luis M., Rohan, Thomas, Sesso, Howard D., Severi, Gianluca, Sheikh, Mahdi, Sinha, Rashmi, Shu, Xiao-Ou, Stevens, Victoria L., Tammemägi, Martin C., Tinker, Lesley F., Visvanathan, Kala, Wang, Ying, Wang, Renwei, Weinstein, Stephanie J., White, Emily, Wilson, David, Yuan, Jian-Min, Zhang, Xuehong, Zheng, Wei, Amos, Christopher I., Brennan, Paul, Johansson, Mattias, Hung, Rayjean J., Robbins, Hilary A., Alcala, Karine, Moez, Elham Khodayari, Guida, Florence, Thomas, Sera, Zahed, Hana, Warkentin, Matthew T., Smith-Byrne, Karl, Brhane, Yonathan, Muller, David, Feng, Xiaoshuang, Albanes, Demetrius, Aldrich, Melinda C., Arslan, Alan A., Bassett, Julie, Berg, Christine D., Cai, Qiuyin, Chen, Chu, Davies, Michael P.A., Diergaarde, Brenda, Field, John K., Freedman, Neal D., Huang, Wen-Yi, Johansson, Mikael, Jones, Michael, Koh, Woon-Puay, Lam, Stephen, Lan, Qing, Langhammer, Arnulf, Liao, Linda M., Liu, Geoffrey, Malekzadeh, Reza, Milne, Roger L., Montuenga, Luis M., Rohan, Thomas, Sesso, Howard D., Severi, Gianluca, Sheikh, Mahdi, Sinha, Rashmi, Shu, Xiao-Ou, Stevens, Victoria L., Tammemägi, Martin C., Tinker, Lesley F., Visvanathan, Kala, Wang, Ying, Wang, Renwei, Weinstein, Stephanie J., White, Emily, Wilson, David, Yuan, Jian-Min, Zhang, Xuehong, Zheng, Wei, Amos, Christopher I., Brennan, Paul, Johansson, Mattias, and Hung, Rayjean J.
- Abstract
The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
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- 2023
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5. Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization
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King, Sontoria D., Veliginti, Swathi, Brouwers, Martijn C G J, Ren, Zhewen, Zheng, Wei, Setiawan, Veronica W., Wilkens, Lynne R., Shu, Xiao-Ou, Arslan, Alan A., Beane Freeman, Laura E., Bracci, Paige M., Canzian, Federico, Du, Mengmeng, Gallinger, Steven J., Giles, Graham G., Goodman, Phyllis J., Haiman, Christopher A., Kogevinas, Manolis, Kooperberg, Charles, LeMarchand, Loic, Neale, Rachel E., Visvanathan, Kala, White, Emily, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Berndt, Sonja I., Brais, Lauren K., Brennan, Paul, Buring, Julie E., Rabe, Kari G., Bamlet, William R., Chanock, Stephen J., Fuchs, Charles S., Gaziano, J Michael, Giovannucci, Edward L., Hackert, Thilo, Hassan, Manal M., Katzke, Verena, Kurtz, Robert C., Lee, I-Min, Malats, Núria, Murphy, Neil, Oberg, Ann L., Orlow, Irene, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Wactawski-Wende, Jean, Wang, Xiaoliang, Wentzensen, Nicolas, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Yu, Kai, Wolpin, Brian M., Duell, Eric J., Li, Donghui, Hung, Rayjean J., Perdomo, Sandra, McCullough, Marjorie L., Freedman, Neal D., Patel, Alpa V., Peters, Ulrike, Riboli, Elio, Sund, Malin, Tjønneland, Anne, Zhong, Jun, Van Den Eeden, Stephen K., Kraft, Peter, Risch, Harvey A., Amundadottir, Laufey T., Klein, Alison P., Stolzenberg-Solomon, Rachael Z., Antwi, Samuel O., King, Sontoria D., Veliginti, Swathi, Brouwers, Martijn C G J, Ren, Zhewen, Zheng, Wei, Setiawan, Veronica W., Wilkens, Lynne R., Shu, Xiao-Ou, Arslan, Alan A., Beane Freeman, Laura E., Bracci, Paige M., Canzian, Federico, Du, Mengmeng, Gallinger, Steven J., Giles, Graham G., Goodman, Phyllis J., Haiman, Christopher A., Kogevinas, Manolis, Kooperberg, Charles, LeMarchand, Loic, Neale, Rachel E., Visvanathan, Kala, White, Emily, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Berndt, Sonja I., Brais, Lauren K., Brennan, Paul, Buring, Julie E., Rabe, Kari G., Bamlet, William R., Chanock, Stephen J., Fuchs, Charles S., Gaziano, J Michael, Giovannucci, Edward L., Hackert, Thilo, Hassan, Manal M., Katzke, Verena, Kurtz, Robert C., Lee, I-Min, Malats, Núria, Murphy, Neil, Oberg, Ann L., Orlow, Irene, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Wactawski-Wende, Jean, Wang, Xiaoliang, Wentzensen, Nicolas, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Yu, Kai, Wolpin, Brian M., Duell, Eric J., Li, Donghui, Hung, Rayjean J., Perdomo, Sandra, McCullough, Marjorie L., Freedman, Neal D., Patel, Alpa V., Peters, Ulrike, Riboli, Elio, Sund, Malin, Tjønneland, Anne, Zhong, Jun, Van Den Eeden, Stephen K., Kraft, Peter, Risch, Harvey A., Amundadottir, Laufey T., Klein, Alison P., Stolzenberg-Solomon, Rachael Z., and Antwi, Samuel O.
- Abstract
BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.
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- 2023
- Full Text
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6. Sex-Specific Associations between Adiponectin and Leptin Signaling and Pancreatic Cancer Survival.
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Babic, Ana, Babic, Ana, Wang, Qiao-Li, Lee, Alice, Yuan, Chen, Rifai, Nader, Luo, Juhua, Tabung, Fred, Wactawski-Wende, Jean, Saquib, Nazmus, Kim, Jihye, Kraft, Peter, Sesso, Howard, Buring, Julie, Giovannucci, Edward, Manson, JoAnn, Stampfer, Meir, Ng, Kimmie, Fuchs, Charles, Wolpin, Brian, Shadyab, Aladdin, Babic, Ana, Babic, Ana, Wang, Qiao-Li, Lee, Alice, Yuan, Chen, Rifai, Nader, Luo, Juhua, Tabung, Fred, Wactawski-Wende, Jean, Saquib, Nazmus, Kim, Jihye, Kraft, Peter, Sesso, Howard, Buring, Julie, Giovannucci, Edward, Manson, JoAnn, Stampfer, Meir, Ng, Kimmie, Fuchs, Charles, Wolpin, Brian, and Shadyab, Aladdin
- Abstract
BACKGROUND: Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with patient survival has not been investigated. METHODS: Adipokine levels were measured in prospectively collected samples from 472 patients with pancreatic cancer. Because of sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 SNPs in adiponectin receptor genes (ADIPOR1 and ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR). RESULTS: Adiponectin levels were inversely associated with survival in women [HR, 1.71; 95% confidence interval (CI), 1.15-2.54]; comparing top with bottom quartile but not in men (HR, 0.89; 95% CI, 0.46-1.70). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR, 0.66; 95% CI, 0.51-0.84, and HR, 1.33; 95% CI, 1.12-1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population [HRs, 1.54 (95% CI, 1.25-1.90), 0.72 (95% CI, 0.59-0.88), and 0.70 (95% CI, 0.56-0.89), respectively], whereas rs11585329 was associated with survival in men only (HR, 0.39; 95% CI, 0.23-0.66; Pinteraction = 0.0002). CONCLUSIONS: High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival. IMPACT: Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner.
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- 2023
7. Whole-genome sequencing reveals host factors underlying critical COVID-19
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Kousathanas, A., Pairo-Castineira, E., Rawlik, K., Stuckey, A., Odhams, C. A., Walker, S., Russell, C. D., Malinauskas, T., Wu, Y., Millar, J., Shen, X., Elliott, K. S., Griffiths, F., Oosthuyzen, W., Morrice, K., Keating, S., Wang, B., Rhodes, D., Klaric, L., Zechner, M., Parkinson, N., Siddiq, A., Goddard, P., Donovan, S., Maslove, D., Nichol, A., Semple, M. G., Zainy, T., Maleady-Crowe, F., Todd, L., Salehi, S., Knight, J., Elgar, G., Chan, G., Arumugam, P., Patch, C., Rendon, A., Bentley, D., Kingsley, C., Kosmicki, J. A., Horowitz, J. E., Baras, A., Abecasis, G. R., Ferreira, M. A. R., Justice, A., Mirshahi, T., Oetjens, M., Rader, D. J., Ritchie, M. D., Verma, A., Fowler, T. A., Shankar-Hari, M., Summers, C., Hinds, C., Horby, P., Mcauley, D., Montgomery, H., Openshaw, P. J. M., Elliott, P., Walsh, T., Tenesa, A., Fawkes, A., Murphy, L., Rowan, K., Ponting, C. P., Vitart, V., Wilson, J. F., Yang, J., Bretherick, A. D., Scott, R. H., Hendry, S. C., Moutsianas, L., Law, A., Caulfield, M. J., Baillie, J. K., Begg, C., Ling, L., Pereira, A. C., Aravindan, L., Armstrong, R., Biggs, H., Boz, C., Brown, A., Clark, R., Coutts, A., Coyle, J., Cullum, L., Das, S., Day, N., Donnelly, L., Duncan, E., Finernan, P., Fourman, M. H., Furlong, A., Furniss, J., Gallagher, B., Gilchrist, T., Golightly, A., Hafezi, K., Hamilton, D., Hendry, R., Law, D., Law, R., Law, S., Lidstone-Scott, R., Macgillivray, L., Maclean, A., Mal, H., Mccafferty, S., Mcmaster, E., Meikle, J., Moore, S. C., Murphy, S., Hellen, M., Zheng, C., Chen, J., Paterson, T., Schon, K., Stenhouse, A., Das, M., Swets, M., Szoor-McElhinney, H., Taneski, F., Turtle, L., Wackett, T., Ward, M., Weaver, J., Wrobel, N., Arbane, G., Bociek, A., Campos, S., Grau, N., Jones, T. O., Lim, R., Marotti, M., Ostermann, M., Whitton, C., Alldis, Z., Astin-Chamberlain, R., Bibi, F., Biddle, J., Blow, S., Bolton, M., Borra, C., Bowles, R., Burton, M., Choudhury, Y., Collier, D., Cox, A., Easthope, A., Ebano, P., Fotiadis, S., Gurasashvili, J., Halls, R., Hartridge, P., Kallon, D., Kassam, J., Lancoma-Malcolm, I., Matharu, M., May, P., Mitchelmore, O., Newman, T., Patel, M., Pheby, J., Pinzuti, I., Prime, Z., Prysyazhna, O., Shiel, J., Taylor, M., Tierney, C., Wood, S., Zak, A., Zongo, O., Bonner, S., Hugill, K., Jones, J., Liggett, S., Headlam, E., Bandla, N., Gellamucho, M., Davies, M., Thompson, C., Abdelrazik, M., Bakthavatsalam, D., Elhassan, M., Ganesan, A., Haldeos, A., Moreno-Cuesta, J., Purohit, D., Vincent, R., Xavier, K., Kumar, R., Frater, Alessia, Saleem, M., Carter, D., Jenkins, S., Lamond, Z., Wall, A., Fernandez-Roman, J., Hamilton, D. O., Johnson, E., Johnston, B., Martinez Guzman, Maria Loreto, Mulla, S., Shaw, D., Waite, A. A. 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S., Templeton, M., Meredith, M., Morris, L., Ryan, L., Clark, A., Sampson, J., Peters, C., Dent, M., Langley, M., Ashraf, Sana, Wei, S., Andrew, A., Bashyal, A., Davidson, N., Hutton, P., Mckechnie, S., Wilson, J., Baptista, D., Crowe, R., Fernandes, R., Herdman-Grant, R., Joseph, A., O'Connor, D., Allen, M., Loveridge, A., Mckenley, I., Morino, E., Naranjo, A., Simms, R., Sollesta, K., Swain, A., Venkatesh, H., Khera, J., Fox, J., Andrew, G., Barclay, L., Callaghan, M., Campbell, R., Clark, S., Hope, D., Marshall, L., Mcculloch, C., Briton, K., Singleton, J., Birch, S., Brimfield, L., Daly, Z., Pogson, D., Rose, S., Nown, A., Battle, C., Brinkworth, E., Harford, R., Murphy, C., Newey, L., Rees, T., Williams, M., Arnold, S., Polgarova, P., Stroud, K., Meaney, E., Jones, M., Ng, A., Agrawal, S., Pathan, N., White, D., Daubney, E., Elston, K., Grauslyte, L., Hussain, M., Phull, M., Pogreban, T., Rosaroso, L., Salciute, E., Franke, G., Wong, J., George, A., de Gordoa, L. 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J., Neale, B. M., Ganna, A., Frater A., Martinez M. L., Smith J., Ashraf S., Singh J., Kay A., Lorusso R., Ali A., Williams H., Barberis L., Wood D. (ORCID:0000-0001-8588-8931), Latif M., Finn S., Taylor A., Tucci A., Adams E. L., Milani L. (ORCID:0000-0003-0218-458X), Valentino F., Mencarelli M. A., Palmieri M. (ORCID:0000-0001-8263-336X), Gori M., Mantovani S., Rossetti B., D'Alessandro M., Franchi F., Donati A., Antinori A. (ORCID:0000-0002-6019-2417), Capasso M., Fiorentino G., Perna R., Sanguinetti M. (ORCID:0000-0002-9780-7059), Masucci L. (ORCID:0000-0002-8358-6726), Lena F. (ORCID:0000-0001-5528-319X), Gabbi C., Botta G., Di Domenico P., Pessina G., Tumbarello M. (ORCID:0000-0002-9519-8552), Di Pietro M. (ORCID:0000-0002-3893-8788), Barbieri C., Lista M., and Petrocelli P.
- Abstract
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
- Published
- 2022
8. A first update on mapping the human genetic architecture of COVID-19
- Author
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Pathak, and Polimanti, Gita A., and Karjalainen, Renato, and Daly, Juha, and Ganna, Mark, and Daly, Andrea, and Stevens, Mark J., and Kanai, Christine, and Liao, Masahiro, and Trankiem, Rachel G., and Balaconis, Amy, and Nguyen, Mary K., and Solomonson, Huy, and Veerapen, Matthew, and Ripatti, Kumar, and Nkambul, Samuli, and Bryant, Lindo, and Sankaran, Sam, and Neale, Vijay G., and Karczewski, Benjamin M., and Martin, Konrad J., and Atkinson, Alicia R., and Tsuo, Elizabeth G., and Baya, Kristin, and Turley, Nikola, and Gupta, Patrick, and Walters, Rahul, and Palmer, Raymond K., and Sarma, Duncan S., and Cheng, Gopal, and Lu, Nathan, and Churchhouse, Wenhan, and Goldstein, Claire, I, and King, Jacqueline, and Zhou, Daniel, and Seed, Wei, and Finucane, Cotton, and Satterstrom, Hilary, Kyle and Andrews, F., and Sloofman, Shea J., and Sealfon, Laura G., and Hoggart, Stuart C., and Underwood, Clive, and Cordioli, Slayton J., and Pirinen, Mattia, and Donner, Matti, and Kivinen, Kati, and Palotie, Katja, and Kaunisto, Aarno, and Harerimana, Mari, and Chwialkowska, Nadia, and Wolford, Karolina, and Roberts, Brooke, and Park, Genevieve, and Ball, Danny, and Coignet, Catherine A., and McCurdy, Marie, and Knight, Shannon, and Partha, Spencer, and Rhead, Raghavendran, and Zhang, Brooke, and Berkowitz, Miao, and Gaddis, Nathan, and Noto, Michael, and Ruiz, Keith, and Pavlovic, Luong, and Hong, Milo, and Rand, Eurie L., and Girshick, Kristin, and Guturu, Ahna, and Baltzell, Harendra, Haug and Niemi, Asher, and Pigazzini, Mari E. K., and Rahmouni, Sara, and Georges, Souad, and Belhaj, Michel, and Guntz, Yasmine, and Claassen, Julien, and Beguin, Sabine, and Gofflot, Yve, and Nkambule, Stephanie, and Nkambul, Lindokuhle, and Cusick, Lindokuhle, and Moutschen, Caroline, and Misset, Michel, and Darcis, Benoit, and Guiot, Gille, and Azarzar, Julien, and Malaise, Samira, and Huynen, Olivier, and Meuris, Pascale, and Thys, Christelle, and Jacques, Marie, and Leonard, Jessica, and Frippiat, Philippe, and Giot, Frederic, and Sauvage, Jean-Baptiste, and Von Frenckell, Anne-Sophie, and Lambermont, Christian, and Nakanishi, Bernard, and Morrison, Tomoko, and Richards, David R., Brent and Butler-Laporte, J., and Forgetta, Guillaume, and Ghosh, Vincenzo, and Laurent, Biswarup, and Henry, Laetitia, and Abdullah, Danielle, and Adeleye, Tala, and Mamlouk, Olumide, and Kimchi, Noor, and Afrasiabi, Nofar, and Rezk, Zaman, and Vulesevic, Nardin, and Bouab, Branka, and Guzman, Meriem, and Petitjean, Charlotte, and Tselios, Loui, and Xue, Chri, and Afilalo, Xiaoqing, and Adra, Jonathan, and Mooser, Darin, and Li, Vincent, and Belisle, Rui, and Lepage, Alexandre, and Ragoussis, Pierre, and Auld, Jianni, and Lathrop, Daniel, Mark and Afilalo, G., and Oliveira, Marc, and Brenner, Maureen, and Brassard, Bluma, and Durand, Nathalie, and Chasse, Madeleine, and Kaufmann, Michael, and Schurr, Daniel E., and Hayward, Erwin, and Richmond, Caroline, and Baillie, Anne, Kenneth and Glessner, J., and Hakonarson, Joseph T., and Chang, Hakon, and Shaw, Xiao, and Below, Douglas M., and Polikowski, Jennifer, and Lauren, Hannah, and Chen, Petty E., and Zhu Wanying and Davis, Hung-Hsin, and Kerchberger, Lea, Eric and Campbell, V., and Porteous, Archie, and Fawns-Ritchie, David J., and Morris, Chloe, and McCormick, Marcela, and North, Joseph B., and Glessner, Kari, and Gignoux, Joseph R., and Wicks, Christopher R., and Crooks, Stephen J., and Barnes, Kristy, and Daya, Kathleen C., and Shortt, Michelle, and Rafaels, Jonathan, and Chavan, Nichola, and Timmers, Sameer, and Wilson, Paul R. 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L., and zu Bentrup, M., Meyer and Conen, F., and Clerc, A., and Marchetti, O., and Guillet, O., and Guyat-Jacques, A., and Foucras, C., and Rime, S., and Chassot, M., and Jaquet, J., and Viollet, M., Merlet and Lannepoudenx, R., and Portopena, Y., and Bochud, L., and Desgranges, P. Y., and Filippidis, F., and Guery, P., and Haefliger, B., and Kampouri, D., and Manuel, E. E., and Munting, O., and Papadimitriou-Olivgeris, A., and Regina, M., and Rochat-Stettler, J., and Suttels, L., and Tadini, V, and Tschopp, E., and Van Singer, J., and Viala, M., and Boillat-Blanco, B., and Brahier, N., and Hugli, T., and Meuwly, O., and Pantet, J. Y., and Nussle, O., Gonseth and Bochud, S., and D'Acremont, M., and Younes, V, Estoppey and Albrich, S., and Suh, W. C., and Cerny, N., and O'Mahony, A., and von Mering, L., and Frischknecht, C., and Kleger, M., and Filipovic, G-R, and Kahlert, M., and Wozniak, C. 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and Corridi, Genni, and Nencioni, Marta, and Croci, Cesira, and Bandini, Leonardo, and Piacentini, Maria, and Desanctis, Paolo, and Cappelli, Elena, and Caldarelli, Silvia, Piero and Canaccini, Gian, and Verzuri, Anna, and Anemoli, Agnese, and Ognibene, Valentina, and Pancrazzi, Agostino, and Lorubbio, Alessandro, and Monforte, Maria, D'Arminio and Miraglia, Antonella, Gaia and Girardis, Federica, and Busani, Massimo, and Venturelli, Stefano, and Antinori, Sophie, and Emiliozzi, Andrea, and Vergori, Arianna, and Francisci, Alessandra, and Schiaroli, Daniela, and Tommasi, Elisabetta, and Paciosi, Andrea, and Scotton, Francesco, Giorgio and Andretta, Pier, and Panese, Francesca, and Scaggiante, Sandro, and Gatti, Renzo, and Della Monica, Francesca, and Piscopo, Matteo, and Capasso, Carmelo, and Russo, Mario, and Andolfo, Roberta, and Iolascon, Immacolata, and Merla, Achille, Fiorentino, Giuseppe, and Castori, Giuseppe, and Carella, Marco, and Aucella, Massimo, and Di Biagio, Filippo, and Bassetti, Antonio, and Masucci, Matteo, and Sanguinetti, Luca, and Guarnaccia, Maurizio, and Valente, Alessandra, and De Vivo, Serafina, and Mandala, Oreste, and Giorli, Marco, and Salerni, Alessia, and Zucchi, Lorenzo, and Parravicini, Patrizia, and Giannattasio, Pierpaolo, and Trotta, Ferdinando, and Coiro, Tullio, and Coviello, Gabriella, and Mussini, Domenico A., and Tavecchia, Cristina, and Belli, Luisa, Ann and Mancarella, Mary, and Crotti, Sandro, and Parati, Lia, and Rizzi, Gianfranco, and Maggiolo, Marco, and Ripamonti, Franco, and La Rovere, Diego, Teresa and Sarzi-Braga, Maria, and Bussotti, Simona, and Ravaglia, Maurizio, and Artuso, Sabrina, and Andreucci, Rosangela, and Perrella, Elena, and Romani, Antonio, and Bergomi, Davide, and Catena, Paola, and Colombo, Emanuele, and Vincenti, Riccardo, and Ferri, Antonella, Grassi, Claudio, and Pessina, Davide, and Poscente, Gloria, and Di Pietro, Monica, and Sabrina, Massimo, and Luchi, Ravaglia, and Dei, Sauro, and Sanarico, Simona, and Gabbi, Maurizio, and Ceri, Chiara, and Pinoli, Stefano, and Raimondi, Pietro, and Biscarini, Francesco, and Stella, Filippo, and Vecchia, Alessandra, and Mantovani, Marco, and Ludovisi, Stefania, and Zanella, Serena, and Cossarizza, Isabella, and Parisi, Andrea, Giuseppe and Baratti, Saverio, and Squeo, Stefano, Maria and Raggi, Gabriella, and Marciano, Pamela, and Perna, Carmen, and Menatti, Rita, and Lena, Elisabetta, and Martinelli, Fabio, and Bachetti, Enrico, and Suardi, Tiziana, and Botta, Claudia, and Di Domenico, Giordano, and Barbieri, Paolo, and Tiseo, Chiara, and Falcone, Giusy, and Acquilini, Marco, and Segala, Donatella, Vladimiro and Petrocelli, Francesco, and Baroni, Paola, and van Heel, Silvia, and Hunt, David A., and van Heel, Karen A., and Trembath, David, and Huang, Richard C., Qin and Martin, Qin, and Mason, Hilary C., and Wright, Dan, and Trivedi, John, and Finer, Bhavi, and Akhtar, Sarah, and Anwar, Shaheen, and Arciero, Mohammad, and Ashraf, Elena, and Breen, Samina, and Chung, Gerome, and Curtis, Raymond, and Chowdhury, Charles J., and Colligan, Maharun, and Deloukas, Grainne, and Durham, Pano, and Griffiths, Ceri, and Hurles, Chri, and Hussain, Matt, and Islam, Shapna, and Khan, Kamrul, and Khan, Ahsan, and Lavery, Amara, and Lee, Cath, Hyuck and Lerner, Sang, and MacArthur, Robin, and MacLaughlin, Daniel, and Martin, Bev, and Miah, Hilary, and Newman, Shefa, and Safa, Bill, and Tahmasebi, Nishat, and Griffiths, Farah, and Smith, Christopher J., and Boughton, Albert, and Li, Andrew P., and LeFaive, Kevin W., and Annis, Jonathon, and Zollner, Aubrey, and Wang, Sebastian, and Beck, Jiongming, and Niavarani, Andrew, and Sharififard, Ahmadreza, and Aliannejad, Bahareh, and Naderpour, Rasoul, and Amirsavadkouhi, Zeinab, and Tadi, Ali, Ansari and Aleagha, Hengameh, Etemadi and Ahmadi, Afshar, and Moghaddam, Saeideh, Behrooz Mohseni and Adamsara, Seyed, and Saeedi, Alireza, and Abdollahi, Morteza, and Hosseini, Hamed, and Chariyavilaskul, Abdolmajid, and Jantarabenjakul, Pajaree, and Putchareon, Watsamon, and Torvorapanit, Opa, and Puthanakit, Pattama, and Hirankarn, Thanyawee, and Sodsai, Nattiya, and Chamnanphon, Pimpayao, and Suttichet, Monpat, and Shotelersuk, Thitima B., and Phokaew, Vorasuk, and Chetruengchai, Chureerat, and Pongpanich, Wanna, and Suchartlikitwong, Monnat, and Nilaratanakul, Pintip, and Brumpton, Voraphoj, and Hveem, Ben M., and Asvold, Kristian, Olav and Willer, Bjorn, and Rogne, Cristen, and Solligard, Tormod, and Franke, Erik, and Claringbould, Lude, and Lopera, Annique, and Warmerdam, Esteban, and van Blokland, Robert, and Boezen, Irene, and Deelen, Marike, and Vonk, Patrick, and Lanting, Judith M., and Ori, Pauline, and Feng, Anil P. S., Anne and Weiss, Yen-Chen, and Karlson, Scott T., and Woolley, Elizabeth W., and Smoller, Ann E., and Murphy, Jordan W., and Meigs, Shawn N., and Green, James B., and Perez, Robert C., and Ascolillo, Emma F., and Thompson, Steven, and Beckmann, Ryan C., and Sebra, Noam D., and Gettler, Robert P., and Salib, Kyle, and Zyndorf, Irene, and Schadt, Marissa, and Collins, Eric E., and Levy, Brett L., and Buxbaum, Te, and Britvan, Joseph D., and Keller, Bari, and Tang, Katherine, and Peruggia, Lara, and Hiester, Michael, and Niblo, Liam L., and Aksentijevich, Kristi, and Labkowsky, Alexandra, and Karp, Alexander, and Zlatopolsky, Avromie, and Jordan, Menachem, and Chaudhary, Daniel M., and Cho, Kumardeep, and Itan, Judy H., and Do, Yuval, and Nadkarni, Ron, and Preuss, Girish N., and Loos, Michael, and Belbin, Ruth J. F., and Abul-Husn, Gillian M., and Kenny, Noura S., and Choi, Eimear E., and O'Reilly, Sam, and Charney, Paul, and Huckins, Alexander W., and Ferreira, Laura M., and Abecasis, Manuel A. R., and Cantor, Goncalo R., and Kosmicki, Michael N., and Horowitz, Jack A., and Baras, Julie E., and Yadav, Ari, and Leader, Ashish, and Gass, Joseph B., and Justice, Matthew C., and Chittoor, Anne E., and Josyula, Geetha, Shilpa and Carey, Navya, and Mirshahi, Dave J., and Hottenga, Tooraj, Jan and Bartels, Jouke, and de Geus, Meike, and Nivard, Eco E. J. C., and Verma, Michel M. 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Rossella, and Mencarelli, Sara, and Pinto, Caterina, Maria and Montagnani, Anna, and Tumbarello, Francesca, and Furini, Mario, and Benetti, Simone, and Zguro, Elisa, and Capitani, Kristina, and Bianchi, Katia, and Lista, Francesco, and Mondelli, Mirjam, Umberto and Bruno, Mario, and Castelli, Raffaele, and Quiros-Roldan, Francesco, and Degli Antoni, Eugenia, and Vaghi, Melania, and Rusconi, Massimo, and Riva, Stefano, and Siano, Agostino, and Gabrieli, Matteo, and Fabbiani, Arianna, and Rossetti, Massimiliano, and Rancan, Barbara, and Bargagli, Ilaria, and Bergantini, Elena, and D'Alessandro, Laura, and Cameli, Miriana, and Bennett, Paolo, and Franchi, David, and Anedda, Federico, and Marcantonio, Federico, and Scolletta, Simona, and Mazzei, Sabino, Antonietta and Guerrini, Maria, and Cantarini, Susanna, and Conticini, Luca, and Frediani, Edoardo, and Tacconi, Bruno, and Spertilli, Danilo, and Feri, Chiara, and Donati, Marco, and Scala, Alice, and Guidelli, Raffaele, and Spargi, Luca, and Corridi, Genni, and Nencioni, Marta, and Croci, Cesira, and Bandini, Leonardo, and Piacentini, Maria, and Desanctis, Paolo, and Cappelli, Elena, and Caldarelli, Silvia, Piero and Canaccini, Gian, and Verzuri, Anna, and Anemoli, Agnese, and Ognibene, Valentina, and Pancrazzi, Agostino, and Lorubbio, Alessandro, and Monforte, Maria, D'Arminio and Miraglia, Antonella, Gaia and Girardis, Federica, and Busani, Massimo, and Venturelli, Stefano, and Antinori, Sophie, and Emiliozzi, Andrea, and Vergori, Arianna, and Francisci, Alessandra, and Schiaroli, Daniela, and Tommasi, Elisabetta, and Paciosi, Andrea, and Scotton, Francesco, Giorgio and Andretta, Pier, and Panese, Francesca, and Scaggiante, Sandro, and Gatti, Renzo, and Della Monica, Francesca, and Piscopo, Matteo, and Capasso, Carmelo, and Russo, Mario, and Andolfo, Roberta, and Iolascon, Immacolata, and Merla, Achille, Fiorentino, Giuseppe, and Castori, Giuseppe, and Carella, Marco, and Aucella, Massimo, and Di Biagio, Filippo, and 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Simona, and Gabbi, Maurizio, and Ceri, Chiara, and Pinoli, Stefano, and Raimondi, Pietro, and Biscarini, Francesco, and Stella, Filippo, and Vecchia, Alessandra, and Mantovani, Marco, and Ludovisi, Stefania, and Zanella, Serena, and Cossarizza, Isabella, and Parisi, Andrea, Giuseppe and Baratti, Saverio, and Squeo, Stefano, Maria and Raggi, Gabriella, and Marciano, Pamela, and Perna, Carmen, and Menatti, Rita, and Lena, Elisabetta, and Martinelli, Fabio, and Bachetti, Enrico, and Suardi, Tiziana, and Botta, Claudia, and Di Domenico, Giordano, and Barbieri, Paolo, and Tiseo, Chiara, and Falcone, Giusy, and Acquilini, Marco, and Segala, Donatella, Vladimiro and Petrocelli, Francesco, and Baroni, Paola, and van Heel, Silvia, and Hunt, David A., and van Heel, Karen A., and Trembath, David, and Huang, Richard C., Qin and Martin, Qin, and Mason, Hilary C., and Wright, Dan, and Trivedi, John, and Finer, Bhavi, and Akhtar, Sarah, and Anwar, Shaheen, and Arciero, Mohammad, and Ashraf, Elena, and Breen, Samina, and Chung, Gerome, and Curtis, Raymond, and Chowdhury, Charles J., and Colligan, Maharun, and Deloukas, Grainne, and Durham, Pano, and Griffiths, Ceri, and Hurles, Chri, and Hussain, Matt, and Islam, Shapna, and Khan, Kamrul, and Khan, Ahsan, and Lavery, Amara, and Lee, Cath, Hyuck and Lerner, Sang, and MacArthur, Robin, and MacLaughlin, Daniel, and Martin, Bev, and Miah, Hilary, and Newman, Shefa, and Safa, Bill, and Tahmasebi, Nishat, and Griffiths, Farah, and Smith, Christopher J., and Boughton, Albert, and Li, Andrew P., and LeFaive, Kevin W., and Annis, Jonathon, and Zollner, Aubrey, and Wang, Sebastian, and Beck, Jiongming, and Niavarani, Andrew, and Sharififard, Ahmadreza, and Aliannejad, Bahareh, and Naderpour, Rasoul, and Amirsavadkouhi, Zeinab, and Tadi, Ali, Ansari and Aleagha, Hengameh, Etemadi and Ahmadi, Afshar, and Moghaddam, Saeideh, Behrooz Mohseni and Adamsara, Seyed, and Saeedi, Alireza, and Abdollahi, Morteza, and Hosseini, Hamed, and Chariyavilaskul, Abdolmajid, and Jantarabenjakul, Pajaree, and Putchareon, Watsamon, and Torvorapanit, Opa, and Puthanakit, Pattama, and Hirankarn, Thanyawee, and Sodsai, Nattiya, and Chamnanphon, Pimpayao, and Suttichet, Monpat, and Shotelersuk, Thitima B., and Phokaew, Vorasuk, and Chetruengchai, Chureerat, and Pongpanich, Wanna, and Suchartlikitwong, Monnat, and Nilaratanakul, Pintip, and Brumpton, Voraphoj, and Hveem, Ben M., and Asvold, Kristian, Olav and Willer, Bjorn, and Rogne, Cristen, and Solligard, Tormod, and Franke, Erik, and Claringbould, Lude, and Lopera, Annique, and Warmerdam, Esteban, and van Blokland, Robert, and Boezen, Irene, and Deelen, Marike, and Vonk, Patrick, and Lanting, Judith M., and Ori, Pauline, and Feng, Anil P. S., Anne and Weiss, Yen-Chen, and Karlson, Scott T., and Woolley, Elizabeth W., and Smoller, Ann E., and Murphy, Jordan W., and Meigs, Shawn N., and Green, James B., and Perez, Robert C., and Ascolillo, Emma F., and Thompson, Steven, and Beckmann, Ryan C., and Sebra, Noam D., and Gettler, Robert P., and Salib, Kyle, and Zyndorf, Irene, and Schadt, Marissa, and Collins, Eric E., and Levy, Brett L., and Buxbaum, Te, and Britvan, Joseph D., and Keller, Bari, and Tang, Katherine, and Peruggia, Lara, and Hiester, Michael, and Niblo, Liam L., and Aksentijevich, Kristi, and Labkowsky, Alexandra, and Karp, Alexander, and Zlatopolsky, Avromie, and Jordan, Menachem, and Chaudhary, Daniel M., and Cho, Kumardeep, and Itan, Judy H., and Do, Yuval, and Nadkarni, Ron, and Preuss, Girish N., and Loos, Michael, and Belbin, Ruth J. F., and Abul-Husn, Gillian M., and Kenny, Noura S., and Choi, Eimear E., and O'Reilly, Sam, and Charney, Paul, and Huckins, Alexander W., and Ferreira, Laura M., and Abecasis, Manuel A. R., and Cantor, Goncalo R., and Kosmicki, Michael N., and Horowitz, Jack A., and Baras, Julie E., and Yadav, Ari, and Leader, Ashish, and Gass, Joseph B., and Justice, Matthew C., and Chittoor, Anne E., and Josyula, Geetha, Shilpa and Carey, Navya, and Mirshahi, Dave J., and Hottenga, Tooraj, Jan and Bartels, Jouke, and de Geus, Meike, and Nivard, Eco E. J. C., and Verma, Michel M. G., and Ritchie, Anurag, and Rader, Marylyn D., and Verma, Daniel, and Lucas, Shefali S., and Bradford, Anastasia, and Li, Yuki, and Abedalthagafi, Binglan, and Al Harthi, Malak, and Alsolm, Fawz, and Abu Safieh, Ebtehal, and Alowayn, Leen, and Alqubaishi, Albandary M., and Al Mutairi, Fatimah, and AlBardis, Amal, and Alotaibi, Hadeel, and Fawzy, Sara, and Alaamery, Mohammad S., and Massadeh, Manal, and Almutairi, Salam, and Alshareef, Mansour, and Suliman, Abdulraheem, and Sawaji, Bandar A., and AlMalik, Mona, and Alqahtani, Abdulaziz, and Baraka, Saleh, and Hasanato, Dona, and Mangul, Rana, and Aljawini, Serghei, and Albesher, Nora, and Alkwai, Nour, and Alswailm, Sarah, and Almohammed, Moneera, and Arabi, Iman, and Mahmoud, Yaseen M., and Khattab, Ebrahim S., and Halawani, Amin K., and Alahmadey, Roaa T., and Albakri, Ziab Z., and Felemban, Jehad K., and Al-Awdah, Walaa A., and Alghamdi, Laila, and AlZahrani, Jahad, and AlDhawi, Deema, and Almalki, Nouf, and Albeladi, Faisal, and Albader, Maha, and AlJohani, Anoud, and Al-Afghani, Sameera, and Barhoush, Hani, and Alghamdi, Eman, and Jung, Bader, and Alrashed, Junghyun, and Zeberg, May, and Maricic, Hugo, and Frithiof, Tomislav, and Hultstrom, Robert, and Lipcsey, Michael, and Tardif, Miklo, and Rooyackers, Nicola, and Grip, Olav, and Helgeland, Jonathan, and Harris, Oyvind, and Magnus, Jennifer R., and Lee, Per, and Trogstad, Yunsung, and Mangino, Lill-Iren S., and Spector, Massimo, and Emma, Tim D., and Moutsianas, Duncan, and Caulfield, Louka, and Scott, Mark J., and Rendon, Richard H., and Kousathanas, Augusto, and Pasko, Athanasio, and Walker, Dorota, and Stuckey, Susan, and Odhams, Alex, and Rhodes, Christopher A., and Fowler, Daniel, and Chan, Tom, and Arumugam, Georgia, and Wilson, Prabhu, and Earle, Daniel J., and Lin, Sarah G., and Arning, Shang-Kuan, and Armstrong, Nicola, and Rudkin, Jacob, and Spencer, Justine K., and Koelling, Chris C. A., and Crook, Nil, and Wyllie, Derrick W., and O'Connell, David H., Marie and Band, Anne, and Callier, Gavin, and Soranzo, Shawneequa, and Zhao, Nicole, Hua and Danesh, Jing, and Di Angelantonio, John, and Butterworth, Emanuele, and Sun, Adam S., and Huffman, Yan, and O'Donnell, Jennifer E., and Peloso, Christopher J., and Cho, Gina, and Gaziano, Kelly, Michael and Ho, J., and Tsao, Yuk-Lam, and Priest, Phil, and Smieszek, Jame, and Polymeropoulos, Sandra P., and Polymeropoulos, Christo, and Polymeropoulos, Vasilio, and Przychodzen, Mihael H., and Fernandez-Cadenas, Bartlomiej P., and Llucia-Carol, Israel, and Cullell, Laia, and Muino, Natalia, and Carcel-Marquez, Elena, and Planas, Jara, and Perez-Tur, Anna M., and DeDiego, Jordi, and Iglesias, Marta L., Lloret and Soriano, Lara, and Rico, Alex, and Aguero, Veronica, and Bedini, Daiana, and Domingo, Josep L., and Robles, Carlo, and Lozano, Veronica, and Ruiz-Jaen, Francisco, and Marquez, Francisca, and Gomez, Leonardo, and Coto, Juan, and Albaiceta, Eliecer, and Garcia-Clemente, Guillermo M., and Dalmau, Marta, and Arranz, David, and Dietl, Maria J., and Serra-Llovich, Beatriz, and Soler, Alex, and Colobran, Pere, and Martin-Nalda, Roger, and Martinez, Andrea, Parra and Bernardo, Alba, and Fiz-Lopez, David, and Arribas, Aida, and De La Cal-Sabater, Elisa, and Rojo, Paloma, and Segura, Silvia, and Gonzalez-Villa, Toma, and Serrano-Heras, Esther, and Marti-Fabregas, Gemma, and Jimenez-Xarrie, Joan, and Mimbrera, Elena, de Felipe and Masjuan, Alicia, and Garcia-Madrona, Jaime, and Dominguez-Mayoral, Sebastian, and Villalonga, Anna, Montaner and Menendez-Valladares, Joan, and Chasman, Paloma, and Sesso, Daniel, and Manson, Howard D., and Buring, JoAnn E., and Ridker, Julie E., and Franco, Paul M., and Lee, Giulianini, and Biesecker, Sulggi, and COVID-19 Host Genetics Initiative, Le, and Picchiotti, Marco, Antonietta and Lo Rizzo, Maria, Giuseppe and Fiorentino, and Claudio and Grassi (ORCID:0000-0001-7253-1685)
- Abstract
N/A
- Published
- 2022
9. Avenging Angel? John Brown, the Harpers Ferry Raid and the 'Irrepressible' Conflict. A Unit of Study for Grades 9-12.
- Author
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National Center for History in the Schools, Los Angeles, CA., Pyne, John, and Sesso, Gloria
- Abstract
This unit deals with the struggle between proslavery and antislavery proponents which exacerbated sectional discord and culminated in secession of the southern states and the Civil War. The lessons would most appropriately be taught as a prelude to the Civil War and as a culmination of units on the heightened sectional conflict resulting from passage of the Fugitive Slave Law (1850), the Kansas-Nebraska Act (1854), "Bleeding Kansas" (1855-56), and the Dred Scott decision (1857). The lessons provide a variety of perspectives on John Brown's Harpers Ferry Raid and the ensuing historical interpretation of his character and purpose. The unit objectives are to: (1) analyze John Brown's motives and beliefs for the decision to invade Harpers Ferry and seize the federal arsenal; (2) explore how John Brown's raid at Harpers Ferry exacerbated sectional tensions and contributed to the coming of the Civil War; (3) analyze John Brown's statements following his capture at Harpers Ferry and evaluate their historical accuracy by comparing his account to the historical record; (4) interpret textual, photographic, and graphic images in their historical context; and (5) evaluate how the paintings and illustrations of John Brown have influenced the interpretation of his actions and determine whether they portray him as a martyr or devil. Teaching materials that apply to National Standards for History are provided. (Contains a 14-item annotated bibliography.) (BT)
- Published
- 1999
10. Duel of Eagles: Conflicts in the Southwest, 1820-1848. A Unit of Study for Grades 8-12.
- Author
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National Center for History in the Schools, Los Angeles, CA., Arevalo, John, Drake, James, Sesso, Gloria, and Vigilante, David
- Abstract
This teaching unit represents a specific "dramatic moment" in history that can allow students to delve into the deeper meanings of selected landmark events and explore their wider context in the great historical narrative. Studying a crucial turning point in history helps students realize that history is an ongoing, open-ended process, and that the decisions made today create the conditions of tomorrow's history. This unit is about the historical episode called the "Duel of Eagles." The Duel of Eagles took place in the Southwest between 1820 and 1848. The guide presents the period from the opening of Spanish Texas to Anglo-American colonization in the early 19th century through the Treaty of Guadalupe Hidalgo in 1848, and chronicles a half-century of conflict between Mexico and the United States. The unit is based on primary sources taken from documents, artifacts, journals, diaries, newspapers, and literature from the period under study. The unit contains teacher background materials that provide an overview of the entire unit and the necessary context, as well as lesson plans with student resources that include a variety of ideas and approaches. Contains an 8-item selected bibliography. (BT)
- Published
- 1996
11. The Great Convergence: The Pueblo and Spaniards Meet. A Unit of Study for Grades 8-12.
- Author
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National Center for History in the Schools, Los Angeles, CA., Arevalo, John, Drake, James, Sesso, Gloria, and Vigilante, David
- Abstract
Focusing on the great convergence of Native Americans and Spaniards in the American Southwest introduces students to the indigenous Anasazi, the Spanish Colonists, and the ensuing conflict of cultures culminating with the Pueblo Revolt of 1680. This unit is based on and uses primary resources taken from documents, artifacts, journals, diaries, newspapers, and literature from the period being studied. It is designed to supplement texts that pay little or no attention to the Southwest region of the United States and makes clear that the Southwest had a complex history that antedated the arrival of English speaking people. The unit includes background materials that provide an overview, lesson plans, and student resources. (BT)
- Published
- 1995
12. Federal Indian Policy in the Gilded Age. Lesson Plan.
- Author
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Pyne, John and Sesso, Gloria
- Abstract
Presents a high school lesson plan about U.S. government policy regarding Native Americans that is based on the National Standards for United States History. Includes a map, a reprint of a painting, and five primary source documents. Provides student objectives and step-by-step instructional procedures. (CFR)
- Published
- 1995
13. The Declaration of Independence: To What Extent Did It Have Meaning for African Americans. Lesson Plan.
- Author
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Pyne, John and Sesso, Gloria
- Abstract
Presents a high school history lesson based on the National Standards for United States History. Considers the effect of the American Revolution and the Declaration of Independence on free and enslaved African Americans. (CFR)
- Published
- 1995
14. Woodrow Wilson and the U.S. Ratification of the Treaty of Versailles. Lesson Plan.
- Author
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Pyne, John and Sesso, Gloria
- Abstract
Presents a high school lesson plan on the struggle over ratification of the Treaty of Versailles and U.S. participation in the League of Nations. Includes a timeline of events, four primary source documents, and biographical portraits of two opposing senators. Provides student objectives and step-by-step instructional procedures. (CFR)
- Published
- 1995
15. Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.
- Author
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Zahed H., Ueland P.M., Midttun O., Milne R.L., Giles G.G., Manjer J., Sandsveden M., Langhammer A., Sorgjerd E.P., Grankvist K., Johansson M., Freedman N.D., Huang W.-Y., Chen C., Prentice R., Stevens V.L., Wang Y., Le Marchand L., Wilkens L.R., Weinstein S.J., Albanes D., Cai Q., Blot W.J., Arslan A.A., Zeleniuch-Jacquotte A., Shu X.-O., Zheng W., Yuan J.-M., Koh W.-P., Visvanathan K., Sesso H.D., Zhang X., Gaziano J.M., Fanidi A., Muller D., Brennan P., Guida F., Robbins H.A., Zahed H., Ueland P.M., Midttun O., Milne R.L., Giles G.G., Manjer J., Sandsveden M., Langhammer A., Sorgjerd E.P., Grankvist K., Johansson M., Freedman N.D., Huang W.-Y., Chen C., Prentice R., Stevens V.L., Wang Y., Le Marchand L., Wilkens L.R., Weinstein S.J., Albanes D., Cai Q., Blot W.J., Arslan A.A., Zeleniuch-Jacquotte A., Shu X.-O., Zheng W., Yuan J.-M., Koh W.-P., Visvanathan K., Sesso H.D., Zhang X., Gaziano J.M., Fanidi A., Muller D., Brennan P., Guida F., and Robbins H.A.
- Abstract
Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was-0.91 standard-deviations lower in women than men (95%CI-0.98;-0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p<0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
- Published
- 2021
16. Mendelian randomization analysis of n-6 polyunsaturated fatty acid levels and pancreatic cancer risk.
- Author
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Ghoneim D.H., Zhu J., Zheng W., Long J., Murff H.J., Ye F., Setiawan V.W., Wilkens L.R., Khankari N.K., Haycock P., Antwi S.O., Yang Y., Arslan A.A., Freeman L.E.B., Bracci P.M., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Scelo G., Visvanathan K., White E., Albane D., Amiano P., Andreott G., Babic A., Bamlet W.R., Berndt S.I., Brais L.K., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Rabe K.G., Chanock S.J., Duggal P., Fuchs C.S., Gaziano J.M., Goggins M.G., Hackert T., Hassan M.M., Helzlsouer K.J., Holly E.A., Hoover R.N., Katske V., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Oberg A.L., Porta M., Rothman N., Sesso H.D., Silverman D.T., Ian T., Wactawski-Wende J., Wang X., Wentzensen N., Yu H., Zeleniuch-Jacquotte A., Yu K., Wolpin B.M., Jacobs E.J., Duell E.J., Risch H.A., Petersen G.M., Amundadottir L.T., Kraft P., Klein A.P., Stolzenberg-Solomon R.Z., Shu X.-O., Wu L., Ghoneim D.H., Zhu J., Zheng W., Long J., Murff H.J., Ye F., Setiawan V.W., Wilkens L.R., Khankari N.K., Haycock P., Antwi S.O., Yang Y., Arslan A.A., Freeman L.E.B., Bracci P.M., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Scelo G., Visvanathan K., White E., Albane D., Amiano P., Andreott G., Babic A., Bamlet W.R., Berndt S.I., Brais L.K., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Rabe K.G., Chanock S.J., Duggal P., Fuchs C.S., Gaziano J.M., Goggins M.G., Hackert T., Hassan M.M., Helzlsouer K.J., Holly E.A., Hoover R.N., Katske V., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Oberg A.L., Porta M., Rothman N., Sesso H.D., Silverman D.T., Ian T., Wactawski-Wende J., Wang X., Wentzensen N., Yu H., Zeleniuch-Jacquotte A., Yu K., Wolpin B.M., Jacobs E.J., Duell E.J., Risch H.A., Petersen G.M., Amundadottir L.T., Kraft P., Klein A.P., Stolzenberg-Solomon R.Z., Shu X.-O., and Wu L.
- Abstract
Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. Method(s): We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Result(s): Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: Linoleic acid odds ratio (OR)1.00, 95% confidence interval (CI) 0.98-1.02; arachidonic acid OR 1.00, 95% CI 0.99-1.01; and dihomo-gamma-linolenic acid OR 0.95, 95% CI 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Conclusion(s): Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.Copyright © 2020 American Association for Cancer Research Inc.. All rights reserved.
- Published
- 2021
17. Genome-wide genediabetes and geneobesity interaction scan in 8,255 cases and 11,900 controls from panscan and PanC4 consortia.
- Author
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Campa D., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A., Bueno-De-Mesquita B., Buring J.E., Chanock S.J., Childs E., Duell E.J., Fuchs C., Michael Gaziano J., Goggins M., Hartge P., Hassam M.H., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Orlow I., Peters U., Porta M., Rabe K.G., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Thompson I.M., Tjonneland A., Trichopoulou A., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Amundadottir L.T., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Chatterjee N., Klein A.P., Li D., Kraft P., Wei P., Tang H., Jiang L., Stolzenberg-Solomon R.Z., Arslan A.A., Beane Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Campa D., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A., Bueno-De-Mesquita B., Buring J.E., Chanock S.J., Childs E., Duell E.J., Fuchs C., Michael Gaziano J., Goggins M., Hartge P., Hassam M.H., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Orlow I., Peters U., Porta M., Rabe K.G., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Thompson I.M., Tjonneland A., Trichopoulou A., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Amundadottir L.T., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Chatterjee N., Klein A.P., Li D., Kraft P., Wei P., Tang H., Jiang L., Stolzenberg-Solomon R.Z., Arslan A.A., Beane Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., and Giles G.G.
- Abstract
Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Method(s): We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index >=30 kg/m2) and diabetes (duration >=3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency >=0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Result(s): No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 106) was observed in the meta-analysis (PGxE 1/4 1.2 106, PJoint 1/4 4.2 107). Conclusion(s): This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may
- Published
- 2021
18. Smoking modifies pancreatic cancer risk loci on 2q21.3.
- Author
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Mocci E., Kundu P., Wheeler W., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A.L., Bueno-De-Mesquita B., Buring J.E., Campa D., Chanock S.J., Childs E.J., Duell E.J., Fuchs C.S., Gaziano J.M., Giovannucci E.L., Goggins M.G., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Panico S., Peters U., Porta M., Rabe K.G., Riboli E., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Stevens V.L., Strobel O., Thompson I.M., Tjonneland A., Trichopoulou A., van Den Eeden S.K., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Yuan F., Zeleniuch-Jacquotte A., Amundadottir L.T., Li D., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Kraft P., Chatterjee N., Klein A.P., Stolzenberg-Solomon R., Mocci E., Kundu P., Wheeler W., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Brennan P., Canzian F., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Blackford A.L., Bueno-De-Mesquita B., Buring J.E., Campa D., Chanock S.J., Childs E.J., Duell E.J., Fuchs C.S., Gaziano J.M., Giovannucci E.L., Goggins M.G., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Hung R.J., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Ng K., Oberg A.L., Panico S., Peters U., Porta M., Rabe K.G., Riboli E., Rothman N., Scelo G., Sesso H.D., Silverman D.T., Stevens V.L., Strobel O., Thompson I.M., Tjonneland A., Trichopoulou A., van Den Eeden S.K., Wactawski-Wende J., Wentzensen N., Wilkens L.R., Yu H., Yuan F., Zeleniuch-Jacquotte A., Amundadottir L.T., Li D., Jacobs E.J., Petersen G.M., Wolpin B.M., Risch H.A., Kraft P., Chatterjee N., Klein A.P., and Stolzenberg-Solomon R.
- Abstract
Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, Pinteraction 1/4 3.08 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 1/4 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Copyright © 2021 American Association for Cancer Research.
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- 2021
19. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.
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Julian-Serrano S., Yuan F., Wheeler W., Benyamin B., Machiela M.J., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Duell E.J., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Shu X.-O., Van Den Eeden S.K., Visvanathan K., Zheng W., Albanes D., Andreotti G., Ardanaz E., Babic A., Berndt S.I., Brais L.K., Brennan P., Bueno-de-Mesquita B., Buring J.E., Chanock S.J., Childs E.J., Chung C.C., Fabianova E., Foretova L., Fuchs C.S., Gaziano J.M., Gentiluomo M., Giovannucci E.L., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holcatova I., Holly E.A., Hung R.I., Janout V., Kurtz R.C., Lee I.-M., Malats N., McKean D., Milne R.L., Newton C.C., Oberg A.L., Perdomo S., Peters U., Porta M., Rothman N., Schulze M.B., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., Weiderpass E., Wenstzensen N., White E., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Zhong J., Kraft P., Li D., Campbell P.T., Petersen G.M., Wolpin B.M., Risch H.A., Amundadottir L.T., Klein A.P., Yu K., Stolzenberg-Solomon R.Z., Julian-Serrano S., Yuan F., Wheeler W., Benyamin B., Machiela M.J., Arslan A.A., Beane-Freeman L.E., Bracci P.M., Duell E.J., Du M., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Marchand L.L., Neale R.E., Shu X.-O., Van Den Eeden S.K., Visvanathan K., Zheng W., Albanes D., Andreotti G., Ardanaz E., Babic A., Berndt S.I., Brais L.K., Brennan P., Bueno-de-Mesquita B., Buring J.E., Chanock S.J., Childs E.J., Chung C.C., Fabianova E., Foretova L., Fuchs C.S., Gaziano J.M., Gentiluomo M., Giovannucci E.L., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holcatova I., Holly E.A., Hung R.I., Janout V., Kurtz R.C., Lee I.-M., Malats N., McKean D., Milne R.L., Newton C.C., Oberg A.L., Perdomo S., Peters U., Porta M., Rothman N., Schulze M.B., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., Weiderpass E., Wenstzensen N., White E., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Zhong J., Kraft P., Li D., Campbell P.T., Petersen G.M., Wolpin B.M., Risch H.A., Amundadottir L.T., Klein A.P., Yu K., and Stolzenberg-Solomon R.Z.
- Abstract
BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVE(S): The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHOD(S): We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (+/-20 kb) for a total of 412 SNPs. RESULT(S): The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSION(S): Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.Copyright Published by Oxford University Press on behalf of the American Society for Nutrition 2021.
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- 2021
20. Genome-wide association study data reveal genetic susceptibility to chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma risk.
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Wang X., Yuan F., Hung R.J., Walsh N., Zhang H., Platz E.A., Wheeler W., Song L., Arslan A.A., Beane Freeman L.E., Bracci P., Canzian F., Du M., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Shi J., Duell E.J., Amundadottir L.T., Li D., Petersen G.M., Wolpin B.M., Risch H.A., Yu K., Klein A.P., Stolzenberg-Solomon R., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Rosendahl J., Scelo G., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Amiano P., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Chanock S.J., Fuchs C.S., Michael Gaziano J., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Katzke V., Kirsten H., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Ng K., Oberg A.L., Porta M., Rabe K.G., Real F.X., Rothman N., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., Wentzensen N., Wang X., Yuan F., Hung R.J., Walsh N., Zhang H., Platz E.A., Wheeler W., Song L., Arslan A.A., Beane Freeman L.E., Bracci P., Canzian F., Du M., Wilkens L.R., Yu H., Zeleniuch-Jacquotte A., Shi J., Duell E.J., Amundadottir L.T., Li D., Petersen G.M., Wolpin B.M., Risch H.A., Yu K., Klein A.P., Stolzenberg-Solomon R., Gallinger S., Giles G.G., Goodman P.J., Kooperberg C., Le Marchand L., Neale R.E., Rosendahl J., Scelo G., Shu X.-O., Visvanathan K., White E., Zheng W., Albanes D., Amiano P., Andreotti G., Babic A., Bamlet W.R., Berndt S.I., Brennan P., Bueno-De-Mesquita B., Buring J.E., Campbell P.T., Chanock S.J., Fuchs C.S., Michael Gaziano J., Goggins M.G., Hackert T., Hartge P., Hassan M.M., Holly E.A., Hoover R.N., Katzke V., Kirsten H., Kurtz R.C., Lee I.-M., Malats N., Milne R.L., Murphy N., Ng K., Oberg A.L., Porta M., Rabe K.G., Real F.X., Rothman N., Sesso H.D., Silverman D.T., Thompson I.M., Wactawski-Wende J., and Wentzensen N.
- Abstract
Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (+500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 x 10-6, respectively). After excluding the 20 PDAC susceptibility regions (+500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P 1/4 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P 1/4 0.22) and primary sclerosing cholangitis (P 1/4 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC.Copyright © 2020 American Association for Cancer Research.
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- 2021
21. A transcriptome-wide association study identifies novel candidate susceptibility genes for pancreatic cancer.
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Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., Chung C.C., Hasan M., Zhang T., Xiao W., Albanes D., Andreotti G., Arslan A.A., Babic A., Bamlet W.R., Beane-Freeman L., Berndt S., Borgida A., Bracci P.M., Brais L., Brennan P., Bueno-De-Mesquita B., Buring J., Canzian F., Childs E.J., Cotterchio M., Du M., Duell E.J., Fuchs C., Gallinger S., Michael Gaziano J., Giles G.G., Giovannucci E., Goggins M., Goodman G.E., Goodman P.J., Haiman C., Hartge P., Helzlsouer K.J., Holly E.A., Klein E.A., Kogevinas M., Kurtz R.J., LeMarchand L., Malats N., Mannisto S., Milne R., Neale R.E., Ng K., Obazee O., Oberg A.L., Orlow I., Patel A.V., Peters U., Porta M., Rothman N., Scelo G., Sesso H.D., Severi G., Sieri S., Silverman D., Sund M., Tjonneland A., Thornquist M.D., Tobias G.S., Trichopoulou A., van Den Eeden S.K., Visvanathan K., Wactawski-Wende J., Wentzensen N., White E., Yu H., Yuan C., Zeleniuch-Jacquotte A., Hoover R., Brown K., Kooperberg C., Risch H.A., Jacobs E.J., Li D., Yu K., Shu X.-O., Chanock S.J., Wolpin B.M., Stolzenberg-Solomon R.Z., Chatterjee N., Klein A.P., Smith J.P., Kraft P., Shi J., Petersen G.M., Zheng W., Amundadottir L.T., Zhong J., Jermusyk A., Wu L., Hoskins J.W., Collins I., Mocci E., Zhang M., Song L., and Chung C.C.
- Abstract
Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Method(s): To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Result(s): We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate <.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22:RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusion(s): By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.Copyright © 2020 Oxford University Press. All rights reserved.
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- 2021
22. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
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Mocci, E, Kundu, P, Wheeler, W, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, AL, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, EJ, Duell, EJ, Fuchs, CS, Gaziano, JM, Giovannucci, EL, Goggins, MG, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Panico, S, Peters, U, Porta, M, Rabe, KG, Riboli, E, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Stevens, VL, Strobel, O, Thompson, IM, Tjonneland, A, Trichopoulou, A, Van den Eeden, SK, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Yuan, F, Zeleniuch-Jacquotte, A, Amundadottir, LT, Li, D, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Kraft, P, Chatterjee, N, Klein, AP, Stolzenberg-Solomon, R, Mocci, E, Kundu, P, Wheeler, W, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, AL, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, EJ, Duell, EJ, Fuchs, CS, Gaziano, JM, Giovannucci, EL, Goggins, MG, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Panico, S, Peters, U, Porta, M, Rabe, KG, Riboli, E, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Stevens, VL, Strobel, O, Thompson, IM, Tjonneland, A, Trichopoulou, A, Van den Eeden, SK, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Yuan, F, Zeleniuch-Jacquotte, A, Amundadottir, LT, Li, D, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Kraft, P, Chatterjee, N, Klein, AP, and Stolzenberg-Solomon, R
- Abstract
Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10-8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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- 2021
23. Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults
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Zahed, H, Johansson, M, Ueland, PM, Midttun, O, Milne, RL, Giles, GG, Manjer, J, Sandsveden, M, Langhammer, A, Sorgjerd, EP, Grankvist, K, Freedman, ND, Huang, W-Y, Chen, C, Prentice, R, Stevens, VL, Wang, Y, Le Marchand, L, Wilkens, LR, Weinstein, SJ, Albanes, D, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, Shu, X-O, Zheng, W, Yuan, J-M, Koh, W-P, Visvanathan, K, Sesso, HD, Zhang, X, Gaziano, JM, Fanidi, A, Muller, D, Brennan, P, Guida, F, Robbins, HA, Zahed, H, Johansson, M, Ueland, PM, Midttun, O, Milne, RL, Giles, GG, Manjer, J, Sandsveden, M, Langhammer, A, Sorgjerd, EP, Grankvist, K, Freedman, ND, Huang, W-Y, Chen, C, Prentice, R, Stevens, VL, Wang, Y, Le Marchand, L, Wilkens, LR, Weinstein, SJ, Albanes, D, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, Shu, X-O, Zheng, W, Yuan, J-M, Koh, W-P, Visvanathan, K, Sesso, HD, Zhang, X, Gaziano, JM, Fanidi, A, Muller, D, Brennan, P, Guida, F, and Robbins, HA
- Abstract
Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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- 2021
24. Direct ink writing of hierarchical porous ultra-high temperature ceramics (ZrB2)
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Sesso, ML, Slater, S, Thornton, J, Franks, GV, Sesso, ML, Slater, S, Thornton, J, and Franks, GV
- Abstract
An approach to producing hierarchical multi‐scale porous ultra‐high temperature ceramics (zirconium diboride, ZrB2) using 3D printing has been developed. Porous ceramic filaments can be 3D printed via Direct Ink Writing (DIW) (paste extrusion). Millimeter scale porosity is created by the 3D printed scaffold filaments. We introduce 20‐micron‐scale porosity into the scaffold filaments with the addition of oil to produce capillary suspension paste inks. Micron‐scale porosity is also developed by partial sintering of the ceramic. The rheological (flow) properties of the capillary suspension paste inks suitable for printing by extrusion through the needle of the 3D printer have been characterized. The samples are strengthened by partial sintering at high temperatures. Complex‐shaped components can be printed and sintered into crack‐free components, but distortion during drying and sintering lead to poor shape and tolerance control. X‐ray tomography is used to characterize the internal structure of the printed components. Printed test bars measured in 4‐point bend testing exhibit high strength to density ratio. Such materials potentially have applications as insulation near very high‐temperature surfaces in aerospace applications.
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- 2021
25. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies
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Julian-Serrano, S, Yuan, F, Wheeler, W, Benyamin, B, Machiela, MJ, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Duell, EJ, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Van den Eeden, SK, Visvanathan, K, Zheng, W, Albanes, D, Andreotti, G, Ardanaz, E, Babic, A, Berndt, S, Brais, LK, Brennan, P, Bueno-de-Mesquita, B, Buring, JE, Chanock, SJ, Childs, EJ, Chung, CC, Fabianova, E, Foretova, L, Fuchs, CS, Gaziano, JM, Gentiluomo, M, Giovannucci, EL, Goggins, MG, Hackert, T, Hartge, P, Hassan, MM, Holcatova, I, Holly, EA, Hung, R, Janout, V, Kurtz, RC, Lee, I-M, Malats, N, McKean, D, Milne, RL, Newton, CC, Oberg, AL, Perdomo, S, Peters, U, Porta, M, Rothman, N, Schulze, MB, Sesso, HD, Silverman, DT, Thompson, IM, Wactawski-Wende, J, Weiderpass, E, Wenstzensen, N, White, E, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Zhong, J, Kraft, P, Li, D, Campbell, PT, Petersen, GM, Wolpin, BM, Risch, HA, Amundadottir, LT, Klein, AP, Yu, K, Stolzenberg-Solomon, RZ, Julian-Serrano, S, Yuan, F, Wheeler, W, Benyamin, B, Machiela, MJ, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Duell, EJ, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Van den Eeden, SK, Visvanathan, K, Zheng, W, Albanes, D, Andreotti, G, Ardanaz, E, Babic, A, Berndt, S, Brais, LK, Brennan, P, Bueno-de-Mesquita, B, Buring, JE, Chanock, SJ, Childs, EJ, Chung, CC, Fabianova, E, Foretova, L, Fuchs, CS, Gaziano, JM, Gentiluomo, M, Giovannucci, EL, Goggins, MG, Hackert, T, Hartge, P, Hassan, MM, Holcatova, I, Holly, EA, Hung, R, Janout, V, Kurtz, RC, Lee, I-M, Malats, N, McKean, D, Milne, RL, Newton, CC, Oberg, AL, Perdomo, S, Peters, U, Porta, M, Rothman, N, Schulze, MB, Sesso, HD, Silverman, DT, Thompson, IM, Wactawski-Wende, J, Weiderpass, E, Wenstzensen, N, White, E, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Zhong, J, Kraft, P, Li, D, Campbell, PT, Petersen, GM, Wolpin, BM, Risch, HA, Amundadottir, LT, Klein, AP, Yu, K, and Stolzenberg-Solomon, RZ
- Abstract
BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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- 2021
26. Elastic plastic fracture mechanics investigation of toughness of wet colloidal particulate materials: Influence of saturation.
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Franks, GV, Sesso, ML, Lam, M, Lu, Y, Xu, L, Franks, GV, Sesso, ML, Lam, M, Lu, Y, and Xu, L
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HYPOTHESIS: Previous use of linear elastic fracture mechanics to estimate toughness of wet particulate materials underestimates the toughness because it does not account for plastic deformation as a dissipation mechanism. Plastic deformation is responsible for the majority of energy dissipated during the fracture of wet colloidal particulate materials. Plastic deformation around the crack tip increases with saturation of the particulate body. The toughness of the body increases with increasing saturation. EXPERIMENTS: Elastic plastic fracture mechanics using the J-integral approach was used for the first time to measure the fracture toughness (JIC) of wet micron sized alumina powder bodies as a function of saturation. The samples were prepared by slip casting. The saturation was controlled by treatment in a humidity chamber. The elastic modulus (E) and the energy dissipated by plastic flow (Apl) were measured in uniaxial compression. The critical stress intensity factor (KIC) was measured using a diametral compression sample with a flaw of known size. The fracture toughness (JIC) was calculated from these measured quantities and the geometry of the specimen. FINDINGS: Elastic plastic fracture mechanics was used for the first time to quantitively account for plastic deformation of wet particulate materials. The linear elastic fracture mechanics approach previously used accounted for less than 1% of the total energy dissipated in fracture. Toughness (JIC) was found to increase with increasing saturation due to plastic deformation that increased with saturation level. The improved understanding of toughness as a function of saturation will aid in providing quantitative analysis of cracking in drying colloidal films and bodies.
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- 2021
27. Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults
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Zahed, Hana, Johansson, Mattias, Ueland, Per M., Midttun, Øivind, Milne, Roger L., Giles, Graham G., Manjer, Jonas, Sandsveden, Malte, Langhammer, Arnulf, Sørgjerd, Elin Pettersen, Grankvist, Kjell, Johansson, Mikael, Freedman, Neal D., Huang, Wen-Yi, Chen, Chu, Prentice, Ross, Stevens, Victoria L., Wang, Ying, Le Marchand, Loic, Wilkens, Lynne R., Weinstein, Stephanie J., Albanes, Demetrius, Cai, Qiuyin, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Shu, Xiao-Ou, Zheng, Wei, Yuan, Jian-Min, Koh, Woon-Puay, Visvanathan, Kala, Sesso, Howard D., Zhang, Xuehong, Gaziano, J. Michael, Fanidi, Anouar, Muller, David, Brennan, Paul, Guida, Florence, Robbins, Hilary A., Zahed, Hana, Johansson, Mattias, Ueland, Per M., Midttun, Øivind, Milne, Roger L., Giles, Graham G., Manjer, Jonas, Sandsveden, Malte, Langhammer, Arnulf, Sørgjerd, Elin Pettersen, Grankvist, Kjell, Johansson, Mikael, Freedman, Neal D., Huang, Wen-Yi, Chen, Chu, Prentice, Ross, Stevens, Victoria L., Wang, Ying, Le Marchand, Loic, Wilkens, Lynne R., Weinstein, Stephanie J., Albanes, Demetrius, Cai, Qiuyin, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Shu, Xiao-Ou, Zheng, Wei, Yuan, Jian-Min, Koh, Woon-Puay, Visvanathan, Kala, Sesso, Howard D., Zhang, Xuehong, Gaziano, J. Michael, Fanidi, Anouar, Muller, David, Brennan, Paul, Guida, Florence, and Robbins, Hilary A.
- Abstract
Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40–80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was − 0.91 standard-deviations lower in women than men (95%CI − 0.98; − 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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- 2021
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28. Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
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Mocci, Evelina, Kundu, Prosenjit, Wheeler, William, Arslan, Alan A., Beane-Freeman, Laura E., Bracci, Paige M., Brennan, Paul, Canzian, Federico, Du, Mengmeng, Gallinger, Steven, Giles, Graham G., Goodman, Phyllis J., Kooperberg, Charles, Le Marchand, Loic, Neale, Rachel E., Shu, Xiao-Ou, Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja, Blackford, Amanda L., Bueno-de-Mesquita, Bas, Buring, Julie E., Campa, Daniele, Chanock, Stephen J., Childs, Erica J., Duell, Eric J., Fuchs, Charles S., Gaziano, J. Michael, Giovannucci, Edward L., Goggins, Michael G., Hartge, Patricia, Hassan, Manal M., Holly, Elizabeth A., Hoover, Robert N., Hung, Rayjean J., Kurtz, Robert C., Lee, I-Min, Malats, Nuria, Milne, Roger L., Ng, Kimmie, Oberg, Ann L., Panico, Salvatore, Peters, Ulrike, Porta, Miquel, Rabe, Kari G., Riboli, Elio, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Silverman, Debra T., Stevens, Victoria L., Strobel, Oliver, Thompson, Ian M., Tjonneland, Anne, Trichopoulou, Antonia, Van den Eeden, Stephen K., Wactawski-Wende, Jean, Wentzensen, Nicolas, Wilkens, Lynne R., Yu, Herbert, Yuan, Fangcheng, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey T., Li, Donghui, Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Kraft, Peter, Chatterjee, Nilanjan, Klein, Alison P., Stolzenberg-Solomon, Rachael, Mocci, Evelina, Kundu, Prosenjit, Wheeler, William, Arslan, Alan A., Beane-Freeman, Laura E., Bracci, Paige M., Brennan, Paul, Canzian, Federico, Du, Mengmeng, Gallinger, Steven, Giles, Graham G., Goodman, Phyllis J., Kooperberg, Charles, Le Marchand, Loic, Neale, Rachel E., Shu, Xiao-Ou, Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja, Blackford, Amanda L., Bueno-de-Mesquita, Bas, Buring, Julie E., Campa, Daniele, Chanock, Stephen J., Childs, Erica J., Duell, Eric J., Fuchs, Charles S., Gaziano, J. Michael, Giovannucci, Edward L., Goggins, Michael G., Hartge, Patricia, Hassan, Manal M., Holly, Elizabeth A., Hoover, Robert N., Hung, Rayjean J., Kurtz, Robert C., Lee, I-Min, Malats, Nuria, Milne, Roger L., Ng, Kimmie, Oberg, Ann L., Panico, Salvatore, Peters, Ulrike, Porta, Miquel, Rabe, Kari G., Riboli, Elio, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Silverman, Debra T., Stevens, Victoria L., Strobel, Oliver, Thompson, Ian M., Tjonneland, Anne, Trichopoulou, Antonia, Van den Eeden, Stephen K., Wactawski-Wende, Jean, Wentzensen, Nicolas, Wilkens, Lynne R., Yu, Herbert, Yuan, Fangcheng, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey T., Li, Donghui, Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Kraft, Peter, Chatterjee, Nilanjan, Klein, Alison P., and Stolzenberg-Solomon, Rachael
- Abstract
Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 similar to 10(-8) was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P-interaction = 3.08 x 10(-9)). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r(2) = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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- 2021
29. Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia
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Tang, H, Jiang, L, Stolzenberg-Solomon, RZ, Arslan, AA, Freeman, LEB, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, A, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, E, Duell, EJ, Fuchs, C, Gaziano, JM, Goggins, M, Hartge, P, Hassam, MH, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Orlow, I, Peters, U, Porta, M, Rabe, KG, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Thompson, IM, Tjonneland, A, Trichopoulou, A, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, LT, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Chatterjee, N, Klein, AP, Li, D, Kraft, P, Wei, P, Tang, H, Jiang, L, Stolzenberg-Solomon, RZ, Arslan, AA, Freeman, LEB, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, S, Blackford, A, Bueno-de-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, E, Duell, EJ, Fuchs, C, Gaziano, JM, Goggins, M, Hartge, P, Hassam, MH, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Ng, K, Oberg, AL, Orlow, I, Peters, U, Porta, M, Rabe, KG, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Thompson, IM, Tjonneland, A, Trichopoulou, A, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Amundadottir, LT, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Chatterjee, N, Klein, AP, Li, D, Kraft, P, and Wei, P
- Abstract
BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7). CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT: This study may con
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- 2020
30. Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk
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Yuan, F, Hung, RJ, Walsh, N, Zhang, H, Platz, EA, Wheeler, W, Song, L, Arslan, AA, Freeman, LEB, Bracci, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Rosendahl, J, Scelo, G, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Amiano, P, Andreotti, G, Babic, A, Bamlet, WR, Berndt, SI, Brennan, P, Bueno-de-Mesquita, B, Buring, JE, Campbell, PT, Chanock, SJ, Fuchs, CS, Gaziano, JM, Goggins, MG, Hackert, T, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Katzke, V, Kirsten, H, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Murphy, N, Ng, K, Oberg, AL, Porta, M, Rabe, KG, Real, FX, Rothman, N, Sesso, HD, Silverman, DT, Thompson, IM, Wactawski-Wende, J, Wang, X, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Shi, J, Duell, EJ, Amundadottir, LT, Li, D, Petersen, GM, Wolpin, BM, Risch, HA, Yu, K, Klein, AP, Stolzenberg-Solomon, R, Yuan, F, Hung, RJ, Walsh, N, Zhang, H, Platz, EA, Wheeler, W, Song, L, Arslan, AA, Freeman, LEB, Bracci, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Rosendahl, J, Scelo, G, Shu, X-O, Visvanathan, K, White, E, Zheng, W, Albanes, D, Amiano, P, Andreotti, G, Babic, A, Bamlet, WR, Berndt, SI, Brennan, P, Bueno-de-Mesquita, B, Buring, JE, Campbell, PT, Chanock, SJ, Fuchs, CS, Gaziano, JM, Goggins, MG, Hackert, T, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Katzke, V, Kirsten, H, Kurtz, RC, Lee, I-M, Malats, N, Milne, RL, Murphy, N, Ng, K, Oberg, AL, Porta, M, Rabe, KG, Real, FX, Rothman, N, Sesso, HD, Silverman, DT, Thompson, IM, Wactawski-Wende, J, Wang, X, Wentzensen, N, Wilkens, LR, Yu, H, Zeleniuch-Jacquotte, A, Shi, J, Duell, EJ, Amundadottir, LT, Li, D, Petersen, GM, Wolpin, BM, Risch, HA, Yu, K, Klein, AP, and Stolzenberg-Solomon, R
- Abstract
Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for infla
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- 2020
31. Direct ink writing of hierarchical porous alumina-stabilized emulsions: Rheology and printability
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Chan, SSL, Sesso, ML, Franks, GV, Chan, SSL, Sesso, ML, and Franks, GV
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Bio‐inspired multi‐scaled (hierarchical) porous structures have remarkable strength and stiffness‐to‐density properties. Direct ink writing (DIW) or robocasting, an additive manufacturing (or also commonly known as 3D printing) material extrusion technique is able to create near‐net‐shaped complex geometries. A new approach of combining DIW, colloidal particle‐stabilized emulsion paste inks and partial densification to create tailored architectures of hierarchical porosity on three scales has been demonstrated. The printed and sintered ceramic lattice structures possess relatively high overall porosity of 78.7% (on average), comprising mainly (64.7%) open porosity. The effects of formulation (surfactant and oil concentrations, solids particle size, and mixing speed) on rheology and pore size and morphology have been investigated. The rheological properties (storage modulus, yield stress, and recovery of storage modulus) of the emulsions have been found to delineate the samples with good shape retention from those that slump. Additionally, the internal features of the sintered structures have been analyzed via X‐ray tomography and scanning electron microscope. The role of emulsion stability on printability and the internal structure of the prints has been investigated.
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- 2020
32. A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer
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Zhong, Jun, Jermusyk, Ashley, Wu, Lang, Hoskins, Jason W., Collins, Irene, Mocci, Evelina, Zhang, Mingfeng, Song, Lei, Chung, Charles C., Zhang, Tongwu, Xiao, Wenming, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Bueno-de-Mesquita, Bas, Buring, Julie, Canzian, Federico, Childs, Erica J., Cotterchio, Michelle, Du, Mengmeng, Duell, Eric J., Fuchs, Charles, Gallinger, Steven, Gaziano, J. Michael, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Holly, Elizabeth A., Klein, Eric A., Kogevinas, Manolis, Kurtz, Robert J., LeMarchand, Loic, Malats, Nuria, Mannisto, Satu, Milne, Roger, Neale, Rachel E., Ng, Kimmie, Obazee, Ofure, Oberg, Ann L., Orlow, Irene, Patel, Alpa, V, Peters, Ulrike, Porta, Miquel, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Sieri, Sabina, Silverman, Debra, Sund, Malin, Tjonneland, Anne, Thornquist, Mark D., Tobias, Geoffrey S., Trichopoulou, Antonia, Van den Eeden, Stephen K., Visvanathan, Kala, Wactawski-Wende, Jean, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yuan, Chen, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Brown, Kevin, Kooperberg, Charles, Risch, Harvey A., Jacobs, Eric J., Li, Donghui, Yu, Kai, Shu, Xiao-Ou, Chanock, Stephen J., Wolpin, Brian M., Stolzenberg-Solomon, Rachael Z., Chatterjee, Nilanjan, Klein, Alison P., Smith, Jill P., Kraft, Peter, Shi, Jianxin, Petersen, Gloria M., Zheng, Wei, Amundadottir, Laufey T., Zhong, Jun, Jermusyk, Ashley, Wu, Lang, Hoskins, Jason W., Collins, Irene, Mocci, Evelina, Zhang, Mingfeng, Song, Lei, Chung, Charles C., Zhang, Tongwu, Xiao, Wenming, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Bueno-de-Mesquita, Bas, Buring, Julie, Canzian, Federico, Childs, Erica J., Cotterchio, Michelle, Du, Mengmeng, Duell, Eric J., Fuchs, Charles, Gallinger, Steven, Gaziano, J. Michael, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Holly, Elizabeth A., Klein, Eric A., Kogevinas, Manolis, Kurtz, Robert J., LeMarchand, Loic, Malats, Nuria, Mannisto, Satu, Milne, Roger, Neale, Rachel E., Ng, Kimmie, Obazee, Ofure, Oberg, Ann L., Orlow, Irene, Patel, Alpa, V, Peters, Ulrike, Porta, Miquel, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Sieri, Sabina, Silverman, Debra, Sund, Malin, Tjonneland, Anne, Thornquist, Mark D., Tobias, Geoffrey S., Trichopoulou, Antonia, Van den Eeden, Stephen K., Visvanathan, Kala, Wactawski-Wende, Jean, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yuan, Chen, Zeleniuch-Jacquotte, Anne, Hoover, Robert, Brown, Kevin, Kooperberg, Charles, Risch, Harvey A., Jacobs, Eric J., Li, Donghui, Yu, Kai, Shu, Xiao-Ou, Chanock, Stephen J., Wolpin, Brian M., Stolzenberg-Solomon, Rachael Z., Chatterjee, Nilanjan, Klein, Alison P., Smith, Jill P., Kraft, Peter, Shi, Jianxin, Petersen, Gloria M., Zheng, Wei, and Amundadottir, Laufey T.
- Abstract
Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEPI) and 11 at six known risk loci (5p15.33: TERT, CLPTMIL, ZDHHCIIB; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTMIL, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
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- 2020
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33. Abdominal and gluteofemoral size and risk of liver cancer: The liver cancer pooling project.
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Florio, Andrea A, Florio, Andrea A, Campbell, Peter T, Zhang, Xuehong, Zeleniuch-Jacquotte, Anne, Wactawski-Wende, Jean, Smith-Warner, Stephanie A, Sinha, Rashmi, Simon, Tracey G, Sesso, Howard D, Schairer, Catherine, Rosenberg, Lynn, Rohan, Thomas E, Robien, Kim, Renehan, Andrew G, Purdue, Mark P, Poynter, Jenny N, Palmer, Julie R, Newton, Christina C, Lu, Yunxia, Linet, Martha S, Liao, Linda M, Lee, I-Min, Koshiol, Jill, Kitahara, Cari M, Kirsh, Victoria A, Hofmann, Jonathan N, Graubard, Barry I, Giovannucci, Edward, Gaziano, John M, Gapstur, Susan M, Freedman, Neal D, Demuth, Jane, Chong, Dawn Q, Chan, Andrew T, Buring, Julie E, Bradshaw, Patrick T, Beane Freeman, Laura E, McGlynn, Katherine A, Petrick, Jessica L, Florio, Andrea A, Florio, Andrea A, Campbell, Peter T, Zhang, Xuehong, Zeleniuch-Jacquotte, Anne, Wactawski-Wende, Jean, Smith-Warner, Stephanie A, Sinha, Rashmi, Simon, Tracey G, Sesso, Howard D, Schairer, Catherine, Rosenberg, Lynn, Rohan, Thomas E, Robien, Kim, Renehan, Andrew G, Purdue, Mark P, Poynter, Jenny N, Palmer, Julie R, Newton, Christina C, Lu, Yunxia, Linet, Martha S, Liao, Linda M, Lee, I-Min, Koshiol, Jill, Kitahara, Cari M, Kirsh, Victoria A, Hofmann, Jonathan N, Graubard, Barry I, Giovannucci, Edward, Gaziano, John M, Gapstur, Susan M, Freedman, Neal D, Demuth, Jane, Chong, Dawn Q, Chan, Andrew T, Buring, Julie E, Bradshaw, Patrick T, Beane Freeman, Laura E, McGlynn, Katherine A, and Petrick, Jessica L
- Abstract
Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to <25 kg/m2 ; HR = 1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements.
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- 2020
34. Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia
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Tang, Hongwei, Jiang, Lai, Stolzenberg-Solomon, Rachael Z., Arslan, Alan A., Freeman, Laura E. Beane, Bracci, Paige M., Brennan, Paul, Canzian, Federico, Du, Mengmeng, Gallinger, Steven, Giles, Graham G., Goodman, Phyllis J., Kooperberg, Charles, Le Marchand, Loic, Neale, Rachel E., Shu, Xiao-Ou, Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja, Blackford, Amanda, Bueno-de-Mesquita, Bas, Buring, Julie E., Campa, Daniele, Chanock, Stephen J., Childs, Erica, Duell, Eric J., Fuchs, Charles, Gaziano, J. Michael, Goggins, Michael, Hartge, Patricia, Hassam, Manal H., Holly, Elizabeth A., Hoover, Robert N., Hung, Rayjean J., Kurtz, Robert C., Lee, I-Min, Malats, Nuria, Milne, Roger L., Ng, Kimmie, Oberg, Ann L., Orlow, Irene, Peters, Ulrike, Porta, Miquel, Rabe, Kari G., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Tjønneland, Anne, Trichopoulou, Antonia, Wactawski-Wende, Jean, Wentzensen, Nicolas, Wilkens, Lynne R., Yu, Herbert, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey T., Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Chatterjee, Nilanjan, Klein, Alison P., Li, Donghui, Kraft, Peter, Wei, Peng, Tang, Hongwei, Jiang, Lai, Stolzenberg-Solomon, Rachael Z., Arslan, Alan A., Freeman, Laura E. Beane, Bracci, Paige M., Brennan, Paul, Canzian, Federico, Du, Mengmeng, Gallinger, Steven, Giles, Graham G., Goodman, Phyllis J., Kooperberg, Charles, Le Marchand, Loic, Neale, Rachel E., Shu, Xiao-Ou, Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja, Blackford, Amanda, Bueno-de-Mesquita, Bas, Buring, Julie E., Campa, Daniele, Chanock, Stephen J., Childs, Erica, Duell, Eric J., Fuchs, Charles, Gaziano, J. Michael, Goggins, Michael, Hartge, Patricia, Hassam, Manal H., Holly, Elizabeth A., Hoover, Robert N., Hung, Rayjean J., Kurtz, Robert C., Lee, I-Min, Malats, Nuria, Milne, Roger L., Ng, Kimmie, Oberg, Ann L., Orlow, Irene, Peters, Ulrike, Porta, Miquel, Rabe, Kari G., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Silverman, Debra T., Thompson, Ian M., Tjønneland, Anne, Trichopoulou, Antonia, Wactawski-Wende, Jean, Wentzensen, Nicolas, Wilkens, Lynne R., Yu, Herbert, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey T., Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Chatterjee, Nilanjan, Klein, Alison P., Li, Donghui, Kraft, Peter, and Wei, Peng
- Abstract
Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index >= 30 kg/m(2)) and diabetes (duration >= 3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency >= 0.005, genotyped in at least one dataset) were analyzed. Case-control ( CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covari- ates. Meta-analysis was applied to combine individual GWAS summary statistics.Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The jointeffect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for theGWAStop hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P <1.25 x 10(-6)) was observed in the meta-analysis (P-GxE = 1.2 x 10(-6), P-Joint = 4.2 x 10(-7)).Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic f
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- 2020
35. Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project
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Jackson, Sarah S., Van Dyke, Alison L., Zhu, Bin, Pfeiffer, Ruth M., Petrick, Jessica L., Adami, Hans-Olov, Albanes, Demetrius, Andreotti, Gabriella, Freeman, Laura E. Beane, de Gonzalez, Amy Berrington, Buring, Julie E., Chan, Andrew T., Chen, Yu, Fraser, Gary E., Freedman, Neal D., Gao, Yu-Tang, Gapstur, Susan M., Gaziano, J. Michael, Giles, Graham G., Grant, Eric J., Grodstein, Francine, Hartge, Patricia, Jenab, Mazda, Kitahara, Cari M., Knutsen, Synnove F., Koh, Woon-Puay, Larsson, Susanna C., Lee, I-Min, Liao, Linda M., Luo, Juhua, McGee, Emma E., Milne, Roger L., Monroe, Kristine R., Neuhouser, Marian L., O'Brien, Katie M., Peters, Ulrike, Poynter, Jenny N., Purdue, Mark P., Robien, Kim, Sandler, Dale P., Sawada, Norie, Schairer, Catherine, Sesso, Howard D., Simon, Tracey G., Sinha, Rashmi, Stolzenberg-Solomon, Rachael Z., Tsugane, Shoichiro, Wang, Renwei, Weiderpass, Elisabete, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Yuan, Jian-Min, Zeleniuch-Jacquotte, Anne, Zhang, Xuehong, McGlynn, Katherine A., Campbell, Peter T., Koshiol, Jill, Jackson, Sarah S., Van Dyke, Alison L., Zhu, Bin, Pfeiffer, Ruth M., Petrick, Jessica L., Adami, Hans-Olov, Albanes, Demetrius, Andreotti, Gabriella, Freeman, Laura E. Beane, de Gonzalez, Amy Berrington, Buring, Julie E., Chan, Andrew T., Chen, Yu, Fraser, Gary E., Freedman, Neal D., Gao, Yu-Tang, Gapstur, Susan M., Gaziano, J. Michael, Giles, Graham G., Grant, Eric J., Grodstein, Francine, Hartge, Patricia, Jenab, Mazda, Kitahara, Cari M., Knutsen, Synnove F., Koh, Woon-Puay, Larsson, Susanna C., Lee, I-Min, Liao, Linda M., Luo, Juhua, McGee, Emma E., Milne, Roger L., Monroe, Kristine R., Neuhouser, Marian L., O'Brien, Katie M., Peters, Ulrike, Poynter, Jenny N., Purdue, Mark P., Robien, Kim, Sandler, Dale P., Sawada, Norie, Schairer, Catherine, Sesso, Howard D., Simon, Tracey G., Sinha, Rashmi, Stolzenberg-Solomon, Rachael Z., Tsugane, Shoichiro, Wang, Renwei, Weiderpass, Elisabete, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Yuan, Jian-Min, Zeleniuch-Jacquotte, Anne, Zhang, Xuehong, McGlynn, Katherine A., Campbell, Peter T., and Koshiol, Jill
- Abstract
Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m(2) increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
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- 2019
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36. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
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Johansson, Mattias, Carreras-Torres, Robert, Scelo, Ghislaine, Purdue, Mark P., Mariosa, Daniela, Muller, David C., Timpson, Nicolas J., Haycock, Philip C., Brown, Kevin M., Wang, Zhaoming, Ye, Yuanqing, Hofmann, Jonathan N., Foll, Matthieu, Gaborieau, Valerie, Machiela, Mitchell J., Colli, Leandro M., Li, Peng, Garnier, Jean-Guillaume, Blanche, Helene, Boland, Anne, Burdette, Laurie, Prokhortchouk, Egor, Skryabin, Konstantin G., Yeager, Meredith, Radojevic-Skodric, Sanja, Ognjanovic, Simona, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Weiderpass, Elisabete, Ljungberg, Borje, Sitaram, Raviprakash Tumkur, Häggström, Christel, Bruinsma, Fiona, Jordan, Susan J., Severi, Gianluca, Winship, Ingrid, Hveem, Kristian, Vatten, Lars J., Fletcher, Tony, Larsson, Susanna C., Wolk, Alicja, Banks, Rosamonde E., Selby, Peter J., Easton, Douglas F., Andreotti, Gabriella, Freeman, Laura E. Beane, Koutros, Stella, Mannisto, Satu, Weinstein, Stephanie, Clark, Peter E., Edwards, Todd L., Lipworth, Loren, Gapstur, Susan M., Stevens, Victoria L., Carol, Hallie, Freedman, Matthew L., Pomerantz, Mark M., Cho, Eunyoung, Wilson, Kathryn M., Gaziano, J. Michael, Sesso, Howard D., Freedman, Neal D., Parker, Alexander S., Eckel-Passow, Jeanette E., Huang, Wen-Yi, Kahnoski, Richard J., Lane, Brian R., Noyes, Sabrina L., Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L., Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E., Eisen, Timothy, Henrion, Marc, Larkin, James, Barman, Poulami, Leibovich, Bradley C., Choueiri, Toni K., Lathrop, G. Mark, Deleuze, Jean-Francois, Gunter, Marc, McKay, James D., Wu, Xifeng, Houlston, Richard S., Chanock, Stephen J., Relton, Caroline, Richards, J. Brent, Martin, Richard M., Smith, George Davey, Brennan, Paul, Johansson, Mattias, Carreras-Torres, Robert, Scelo, Ghislaine, Purdue, Mark P., Mariosa, Daniela, Muller, David C., Timpson, Nicolas J., Haycock, Philip C., Brown, Kevin M., Wang, Zhaoming, Ye, Yuanqing, Hofmann, Jonathan N., Foll, Matthieu, Gaborieau, Valerie, Machiela, Mitchell J., Colli, Leandro M., Li, Peng, Garnier, Jean-Guillaume, Blanche, Helene, Boland, Anne, Burdette, Laurie, Prokhortchouk, Egor, Skryabin, Konstantin G., Yeager, Meredith, Radojevic-Skodric, Sanja, Ognjanovic, Simona, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Weiderpass, Elisabete, Ljungberg, Borje, Sitaram, Raviprakash Tumkur, Häggström, Christel, Bruinsma, Fiona, Jordan, Susan J., Severi, Gianluca, Winship, Ingrid, Hveem, Kristian, Vatten, Lars J., Fletcher, Tony, Larsson, Susanna C., Wolk, Alicja, Banks, Rosamonde E., Selby, Peter J., Easton, Douglas F., Andreotti, Gabriella, Freeman, Laura E. Beane, Koutros, Stella, Mannisto, Satu, Weinstein, Stephanie, Clark, Peter E., Edwards, Todd L., Lipworth, Loren, Gapstur, Susan M., Stevens, Victoria L., Carol, Hallie, Freedman, Matthew L., Pomerantz, Mark M., Cho, Eunyoung, Wilson, Kathryn M., Gaziano, J. Michael, Sesso, Howard D., Freedman, Neal D., Parker, Alexander S., Eckel-Passow, Jeanette E., Huang, Wen-Yi, Kahnoski, Richard J., Lane, Brian R., Noyes, Sabrina L., Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L., Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E., Eisen, Timothy, Henrion, Marc, Larkin, James, Barman, Poulami, Leibovich, Bradley C., Choueiri, Toni K., Lathrop, G. Mark, Deleuze, Jean-Francois, Gunter, Marc, McKay, James D., Wu, Xifeng, Houlston, Richard S., Chanock, Stephen J., Relton, Caroline, Richards, J. Brent, Martin, Richard M., Smith, George Davey, and Brennan, Paul
- Abstract
Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
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- 2019
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37. Smoking, Alcohol, and Biliary Tract Cancer Risk : A Pooling Project of 26 Prospective Studies
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McGee, Emma E., Jackson, Sarah S., Petrick, Jessica L., Van Dyke, Alison L., Adami, Hans-Olov, Albanes, Demetrius, Andreotti, Gabriella, Beane-Freeman, Laura E., de Gonzalez, Amy Berrington, Buring, Julie E., Chan, Andrew T., Chen, Yu, Fraser, Gary E., Freedman, Neal D., Gao, Yu-Tang, Gapstur, Susan M., Gaziano, J. Michael, Giles, Graham G., Grant, Eric J., Grodstein, Francine, Hartge, Patricia, Jenab, Mazda, Kitahara, Cari M., Knutsen, Synnove F., Koh, Woon-Puay, Larsson, Susanna C., Lee, I-Min, Liao, Linda M., Luo, Juhua, Milne, Roger L., Monroe, Kristine R., Neuhouser, Marian L., O'Brien, Katie M., Peters, Ulrike, Poynter, Jenny N., Purdue, Mark P., Robien, Kim, Sandler, Dale P., Sawada, Norie, Schairer, Catherine, Sesso, Howard D., Simon, Tracey G., Sinha, Rashmi, Stolzenberg-Solomon, Rachael, Tsugane, Shoichiro, Wang, Renwei, Weiderpass, Elisabete, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Yuan, Jian-Min, Zeleniuch-Jacquotte, Anne, Zhang, Xuehong, Zhu, Bin, McGlynn, Katherine A., Campbell, Peter T., Koshiol, Jill, McGee, Emma E., Jackson, Sarah S., Petrick, Jessica L., Van Dyke, Alison L., Adami, Hans-Olov, Albanes, Demetrius, Andreotti, Gabriella, Beane-Freeman, Laura E., de Gonzalez, Amy Berrington, Buring, Julie E., Chan, Andrew T., Chen, Yu, Fraser, Gary E., Freedman, Neal D., Gao, Yu-Tang, Gapstur, Susan M., Gaziano, J. Michael, Giles, Graham G., Grant, Eric J., Grodstein, Francine, Hartge, Patricia, Jenab, Mazda, Kitahara, Cari M., Knutsen, Synnove F., Koh, Woon-Puay, Larsson, Susanna C., Lee, I-Min, Liao, Linda M., Luo, Juhua, Milne, Roger L., Monroe, Kristine R., Neuhouser, Marian L., O'Brien, Katie M., Peters, Ulrike, Poynter, Jenny N., Purdue, Mark P., Robien, Kim, Sandler, Dale P., Sawada, Norie, Schairer, Catherine, Sesso, Howard D., Simon, Tracey G., Sinha, Rashmi, Stolzenberg-Solomon, Rachael, Tsugane, Shoichiro, Wang, Renwei, Weiderpass, Elisabete, Weinstein, Stephanie J., White, Emily, Wolk, Alicja, Yuan, Jian-Min, Zeleniuch-Jacquotte, Anne, Zhang, Xuehong, Zhu, Bin, McGlynn, Katherine A., Campbell, Peter T., and Koshiol, Jill
- Abstract
Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided. Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; P-trend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
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- 2019
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38. Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium
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Muller, David C., Larose, Tricia L., Hodge, Allison, Guida, Florence, Langhammer, Arnulf, Grankvist, Kjell, Meyer, Klaus, Cai, Qiuyin, Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Albanes, Demetrius, Giles, Graham G., Sesso, Howard D., Lee, I-Min, Gaziano, J. Michael, Yuan, Jian-Min, Bolton, Judith Hoffman, Buring, Julie E., Visvanathan, Kala, Le Marchand, Loic, Purdue, Mark P., Caporaso, Neil E., Midttun, Oivind, Ueland, Per M., Prentice, Ross L., Weinstein, Stephanie J., Stevens, Victoria L., Zheng, Wei, Blot, William J., Shu, Xiao-Ou, Zhang, Xuehong, Xiang, Yong-Bing, Koh, Woon-Puay, Hveem, Kristian, Thomson, Cynthia A., Pettinger, Mary, Engstrom, Gunnar, Brunnstrom, Hans, Milne, Roger L., Stampfer, Meir J., Han, Jiali, Johansson, Mikael, Brennan, Paul, Severi, Gianluca, Johansson, Mattias, Muller, David C., Larose, Tricia L., Hodge, Allison, Guida, Florence, Langhammer, Arnulf, Grankvist, Kjell, Meyer, Klaus, Cai, Qiuyin, Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Albanes, Demetrius, Giles, Graham G., Sesso, Howard D., Lee, I-Min, Gaziano, J. Michael, Yuan, Jian-Min, Bolton, Judith Hoffman, Buring, Julie E., Visvanathan, Kala, Le Marchand, Loic, Purdue, Mark P., Caporaso, Neil E., Midttun, Oivind, Ueland, Per M., Prentice, Ross L., Weinstein, Stephanie J., Stevens, Victoria L., Zheng, Wei, Blot, William J., Shu, Xiao-Ou, Zhang, Xuehong, Xiang, Yong-Bing, Koh, Woon-Puay, Hveem, Kristian, Thomson, Cynthia A., Pettinger, Mary, Engstrom, Gunnar, Brunnstrom, Hans, Milne, Roger L., Stampfer, Meir J., Han, Jiali, Johansson, Mikael, Brennan, Paul, Severi, Gianluca, and Johansson, Mattias
- Abstract
Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type. Design Nested case-control study. Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States. Participants 5299 patients with incident lung cancer, with individually incidence density matched controls. Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples. Main outcome measure Incident lung cancer diagnosis. Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up. Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.
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- 2019
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39. Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
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Walsh, Naomi, Zhang, Han, Hyland, Paula L., Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J., Collins, Irene, Wang, Zhaoming, Arslan, Alan A., Beane-Freeman, Laura, Bracci, Paige M., Brennan, Paul, Canzian, Federico, Duell, Eric J., Gallinger, Steven, Giles, Graham G., Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hung, Rayjean J., Kooperberg, Charles, Kurtz, Robert C., Malats, Núria, LeMarchand, Loic, Neale, Rachel E., Olson, Sara H., Scelo, Ghislaine, Shu, Xiao O., Van Den Eeden, Stephen K., Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja I., Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-de-Mesquita, Bas, Buring, Julie, Chaffee, Kari G., Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M. Gaziano, J. Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Janout, Vladimir, Klein, Eric A., Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L., Oberg, Ann L., Orlow, Irene, Patel, Alpa V., Peters, Ulrike, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D., Tobias, Geoffrey S., Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Amundadottir, Laufey T., Yu, Kai, Klein, Alison P., Stolzenberg-Solomon, Rachael Z., Walsh, Naomi, Zhang, Han, Hyland, Paula L., Yang, Qi, Mocci, Evelina, Zhang, Mingfeng, Childs, Erica J., Collins, Irene, Wang, Zhaoming, Arslan, Alan A., Beane-Freeman, Laura, Bracci, Paige M., Brennan, Paul, Canzian, Federico, Duell, Eric J., Gallinger, Steven, Giles, Graham G., Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hung, Rayjean J., Kooperberg, Charles, Kurtz, Robert C., Malats, Núria, LeMarchand, Loic, Neale, Rachel E., Olson, Sara H., Scelo, Ghislaine, Shu, Xiao O., Van Den Eeden, Stephen K., Visvanathan, Kala, White, Emily, Zheng, Wei, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Bamlet, William R., Berndt, Sonja I., Borgida, Ayelet, Boutron-Ruault, Marie-Christine, Brais, Lauren, Bueno-de-Mesquita, Bas, Buring, Julie, Chaffee, Kari G., Chanock, Stephen, Cleary, Sean, Cotterchio, Michelle, Foretova, Lenka, Fuchs, Charles, M. Gaziano, J. Michael, Giovannucci, Edward, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Janout, Vladimir, Klein, Eric A., Laheru, Daniel, Lee, I-Min, Lu, Lingeng, Mannisto, Satu, Milne, Roger L., Oberg, Ann L., Orlow, Irene, Patel, Alpa V., Peters, Ulrike, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Sesso, Howard D., Severi, Gianluca, Silverman, Debra, Strobel, Oliver, Sund, Malin, Thornquist, Mark D., Tobias, Geoffrey S., Wactawski-Wende, Jean, Wareham, Nick, Weiderpass, Elisabete, Wentzensen, Nicolas, Wheeler, William, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Kraft, Peter, Li, Donghui, Jacobs, Eric J., Petersen, Gloria M., Wolpin, Brian M., Risch, Harvey A., Amundadottir, Laufey T., Yu, Kai, Klein, Alison P., and Stolzenberg-Solomon, Rachael Z.
- Abstract
Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
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- 2019
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40. Sex specific associations in genome wide association analysis of renal cell carcinoma
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Laskar, Ruhina S, Muller, David C, Li, Peng, Machiela, Mitchell J, Ye, Yuanqing, Gaborieau, Valerie, Foll, Matthieu, Hofmann, Jonathan N, Colli, Leandro, Sampson, Joshua N, Wang, Zhaoming, Bacq-Daian, Delphine, Boland, Anne, Abedi-Ardekani, Behnoush, Durand, Geoffroy, Le Calvez-Kelm, Florence, Robinot, Nivonirina, Blanche, Helene, Prokhortchouk, Egor, Skryabin, Konstantin G, Burdett, Laurie, Yeager, Meredith, Radojevic-Skodric, Sanja, Savic, Slavisa, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Rascu, Stefan, Mukeria, Anush, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Świątkowska, Beata, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Trichopoulou, Antonia, Riboli, Elio, Overvad, Kim, Panico, Salvatore, Ljungberg, Börje, Tumkur Sitaram, Raviprakash, Giles, Graham G, Milne, Roger L, Severi, Gianluca, Bruinsma, Fiona, Fletcher, Tony, Koppova, Kvetoslava, Larsson, Susanna C, Wolk, Alicja, Banks, Rosamonde E, Selby, Peter J, Easton, Douglas F, Pharoah, Paul, Andreotti, Gabriella, Beane Freeman, Laura E, Koutros, Stella, Albanes, Demetrius, Männistö, Satu, Weinstein, Stephanie, Clark, Peter E, Edwards, Todd L, Lipworth, Loren, Carol, Hallie, Freedman, Matthew L, Pomerantz, Mark M, Cho, Eunyoung, Kraft, Peter, Preston, Mark A, Wilson, Kathryn M, Michael Gaziano, J, Sesso, Howard D, Black, Amanda, Freedman, Neal D, Huang, Wen-Yi, Anema, John G, Kahnoski, Richard J, Lane, Brian R, Noyes, Sabrina L, Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L, Johnson, Lisa, Luo, Juhua, Chow, Wong-Ho, Moore, Lee E, Choueiri, Toni K, Wood, Christopher, Johansson, Mattias, McKay, James D, Brown, Kevin M, Rothman, Nathaniel, Lathrop, Mark G, Deleuze, Jean-Francois, Wu, Xifeng, Brennan, Paul, Chanock, Stephen J, Purdue, Mark P, Scelo, Ghislaine, Laskar, Ruhina S, Muller, David C, Li, Peng, Machiela, Mitchell J, Ye, Yuanqing, Gaborieau, Valerie, Foll, Matthieu, Hofmann, Jonathan N, Colli, Leandro, Sampson, Joshua N, Wang, Zhaoming, Bacq-Daian, Delphine, Boland, Anne, Abedi-Ardekani, Behnoush, Durand, Geoffroy, Le Calvez-Kelm, Florence, Robinot, Nivonirina, Blanche, Helene, Prokhortchouk, Egor, Skryabin, Konstantin G, Burdett, Laurie, Yeager, Meredith, Radojevic-Skodric, Sanja, Savic, Slavisa, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Rascu, Stefan, Mukeria, Anush, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Świątkowska, Beata, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Trichopoulou, Antonia, Riboli, Elio, Overvad, Kim, Panico, Salvatore, Ljungberg, Börje, Tumkur Sitaram, Raviprakash, Giles, Graham G, Milne, Roger L, Severi, Gianluca, Bruinsma, Fiona, Fletcher, Tony, Koppova, Kvetoslava, Larsson, Susanna C, Wolk, Alicja, Banks, Rosamonde E, Selby, Peter J, Easton, Douglas F, Pharoah, Paul, Andreotti, Gabriella, Beane Freeman, Laura E, Koutros, Stella, Albanes, Demetrius, Männistö, Satu, Weinstein, Stephanie, Clark, Peter E, Edwards, Todd L, Lipworth, Loren, Carol, Hallie, Freedman, Matthew L, Pomerantz, Mark M, Cho, Eunyoung, Kraft, Peter, Preston, Mark A, Wilson, Kathryn M, Michael Gaziano, J, Sesso, Howard D, Black, Amanda, Freedman, Neal D, Huang, Wen-Yi, Anema, John G, Kahnoski, Richard J, Lane, Brian R, Noyes, Sabrina L, Petillo, David, Teh, Bin Tean, Peters, Ulrike, White, Emily, Anderson, Garnet L, Johnson, Lisa, Luo, Juhua, Chow, Wong-Ho, Moore, Lee E, Choueiri, Toni K, Wood, Christopher, Johansson, Mattias, McKay, James D, Brown, Kevin M, Rothman, Nathaniel, Lathrop, Mark G, Deleuze, Jean-Francois, Wu, Xifeng, Brennan, Paul, Chanock, Stephen J, Purdue, Mark P, and Scelo, Ghislaine
- Abstract
Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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- 2019
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41. Is high vitamin B12 status a cause of lung cancer?
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Fanidi, Anouar, Carreras-Torres, Robert, Larose, Tricia L., Yuan, Jian-Min, Stevens, Victoria L., Weinstein, Stephanie J., Albanes, Demetrius, Prentice, Ross, Pettinger, Mary, Cai, Qiuyin, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, McCullough, Marjorie L., Le Marchand, Loic, Wilkens, Lynne R., Haiman, Christopher A., Zhang, Xuehong, Stampfer, Meir J., Smith-Warner, Stephanie A., Giovannucci, Edward, Giles, Graham G., Hodge, Allison M., Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Langhammer, Arnulf, Brumpton, Ben M., Wang, Renwei, Gao, Yu-Tang, Ericson, Ulrika, Bojesen, Stig E., Arnold, Susanne M., Koh, Woon-Puay, Shu, Xiao-Ou, Xiang, Yong-Bing, Li, Honglan, Zheng, Wei, Lan, Qing, Visvanathan, Kala, Hoffman-Bolton, Judith, Ueland, Per M., Midttun, Oivind, Caporaso, Neil E., Purdue, Mark, Freedman, Neal D., Buring, Julie E., Lee, I-Min, Sesso, Howard D., Gaziano, J. Michael, Manjer, Jonas, Relton, Caroline L., Hung, Rayjean J., Amos, Chris, I, Johansson, Mattias, Brennan, Paul, Fanidi, Anouar, Carreras-Torres, Robert, Larose, Tricia L., Yuan, Jian-Min, Stevens, Victoria L., Weinstein, Stephanie J., Albanes, Demetrius, Prentice, Ross, Pettinger, Mary, Cai, Qiuyin, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, McCullough, Marjorie L., Le Marchand, Loic, Wilkens, Lynne R., Haiman, Christopher A., Zhang, Xuehong, Stampfer, Meir J., Smith-Warner, Stephanie A., Giovannucci, Edward, Giles, Graham G., Hodge, Allison M., Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Langhammer, Arnulf, Brumpton, Ben M., Wang, Renwei, Gao, Yu-Tang, Ericson, Ulrika, Bojesen, Stig E., Arnold, Susanne M., Koh, Woon-Puay, Shu, Xiao-Ou, Xiang, Yong-Bing, Li, Honglan, Zheng, Wei, Lan, Qing, Visvanathan, Kala, Hoffman-Bolton, Judith, Ueland, Per M., Midttun, Oivind, Caporaso, Neil E., Purdue, Mark, Freedman, Neal D., Buring, Julie E., Lee, I-Min, Sesso, Howard D., Gaziano, J. Michael, Manjer, Jonas, Relton, Caroline L., Hung, Rayjean J., Amos, Chris, I, Johansson, Mattias, and Brennan, Paul
- Abstract
Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
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- 2019
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42. Is high vitamin B12 status a cause of lung cancer?
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Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, Brennan, P, Fanidi, A, Carreras-Torres, R, Larose, TL, Yuan, J-M, Stevens, VL, Weinstein, SJ, Albanes, D, Prentice, R, Pettinger, M, Cai, Q, Blot, WJ, Arslan, AA, Zeleniuch-Jacquotte, A, McCullough, ML, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Smith-Warner, SA, Giovannucci, E, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Brumpton, BM, Wang, R, Gao, Y-T, Ericson, U, Bojesen, SE, Arnold, SM, Koh, W-P, Shu, X-O, Xiang, Y-B, Li, H, Zheng, W, Lan, Q, Visvanathan, K, Hoffman-Bolton, J, Ueland, PM, Midttun, O, Caporaso, NE, Purdue, M, Freedman, ND, Buring, JE, Lee, I-M, Sesso, HD, Gaziano, JM, Manjer, J, Relton, CL, Hung, RJ, Amos, C, and Brennan, P
- Abstract
Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
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- 2019
43. Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials
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Seidu, S, Kunutsor, SK, Sesso, HD, Gaziano, JM, Buring, JE, Roncaglioni, MC, Khunti, K, Seidu, S, Kunutsor, SK, Sesso, HD, Gaziano, JM, Buring, JE, Roncaglioni, MC, and Khunti, K
- Abstract
BACKGROUND: The clinical benefit of aspirin for the primary prevention of cardiovascular disease (CVD) in diabetes remains uncertain. To evaluate the efficacy and safety of aspirin for the primary prevention of cardiovascular outcomes and all-cause mortality events in people with diabetes, we conducted an updated meta-analysis of published randomised controlled trials (RCTs) and a pooled analysis of individual participant data (IPD) from three trials. METHODS: Randomised controlled trials of aspirin compared with placebo (or no treatment) in participants with diabetes with no known CVD were identified from MEDLINE, Embase, Cochrane Library, and manual search of bibliographies to January 2019. Relative risks with 95% confidence intervals were used as the summary measures of associations. RESULTS: We included 12 RCTs based on 34,227 participants with a median treatment duration of 5.0 years. Comparing aspirin use with no aspirin, there was a significant reduction in risk of major adverse cardiovascular events (MACE)0.89 (0.83-0.95), with a number needed to treat (NNT)of 95 (95% CI 61 to 208) to prevent one MACE over 5 years average follow-up. Evidence was lacking of heterogeneity and publication bias among contributing trials for MACE. Aspirin use had no effect on other endpoints including all-cause mortality; however, there was a significant reduction in stroke for aspirin dosage ≤ 100 mg/day 0.75 (0.59-0.95). There were no significant effects of aspirin use on major bleeding and other bleeding events, though some of the estimates were imprecise. Pooled IPD from the three trials (2306 participants) showed no significant evidence of an effect of aspirin on any of the outcomes evaluated; however, aspirin reduced the risk of MACE in non-smokers 0.70 (0.51-0.96) with a NNT of 33 (95% CI 20 to 246) to prevent one MACE. CONCLUSIONS: Aspirin has potential benefits in cardiovascular primary prevention in diabetes. The use of low dose aspirin may need to be individualised and
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- 2019
44. Corrigendum re 'Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma' : [Eur Urol 2017;72:747-54
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Machiela, Mitchell J, Hofmann, Jonathan N, Carreras-Torres, Robert, Brown, Kevin M, Johansson, Mattias, Wang, Zhaoming, Foll, Matthieu, Li, Peng, Rothman, Nathaniel, Savage, Sharon A, Gaborieau, Valerie, McKay, James D, Ye, Yuanqing, Henrion, Marc, Bruinsma, Fiona, Jordan, Susan, Severi, Gianluca, Hveem, Kristian, Vatten, Lars J, Fletcher, Tony, Koppova, Kvetoslava, Larsson, Susanna C, Wolk, Alicja, Banks, Rosamonde E, Selby, Peter J, Easton, Douglas F, Pharoah, Paul, Andreotti, Gabriella, Freeman, Laura E Beane, Koutros, Stella, Albanes, Demetrius, Mannisto, Satu, Weinstein, Stephanie, Clark, Peter E, Edwards, Todd E, Lipworth, Loren, Gapstur, Susan M, Stevens, Victoria L, Carol, Hallie, Freedman, Matthew L, Pomerantz, Mark M, Cho, Eunyoung, Kraft, Peter, Preston, Mark A, Wilson, Kathryn M, Gaziano, J Michael, Sesso, Howard S, Black, Amanda, Freedman, Neal D, Huang, Wen-Yi, Anema, John G, Kahnoski, Richard J, Lane, Brian R, Noyes, Sabrina L, Petillo, David, Colli, Leandro M, Sampson, Joshua N, Besse, Celine, Blanche, Helene, Boland, Anne, Burdette, Laurie, Prokhortchouk, Egor, Skryabin, Konstantin G, Yeager, Meredith, Mijuskovic, Mirjana, Ognjanovic, Miodrag, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Szeszenia-Dabrowska, Neonila, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Bueno-de-Mesquita, H B As, Canzian, Federico, Duell, Eric J, Ljungberg, Börje, Sitaram, Raviprakash T, Peters, Ulrike, White, Emily, Anderson, Garnet L, Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E, Wood, Christopher, Eisen, Timothy, Larkin, James, Choueiri, Toni K, Lathrop, G Mark, Teh, Bin Tean, Deleuze, Jean-Francois, Wu, Xifeng, Houlston, Richard S, Brennan, Paul, Chanock, Stephen J, Scelo, Ghislaine, Purdue, Mark P, Machiela, Mitchell J, Hofmann, Jonathan N, Carreras-Torres, Robert, Brown, Kevin M, Johansson, Mattias, Wang, Zhaoming, Foll, Matthieu, Li, Peng, Rothman, Nathaniel, Savage, Sharon A, Gaborieau, Valerie, McKay, James D, Ye, Yuanqing, Henrion, Marc, Bruinsma, Fiona, Jordan, Susan, Severi, Gianluca, Hveem, Kristian, Vatten, Lars J, Fletcher, Tony, Koppova, Kvetoslava, Larsson, Susanna C, Wolk, Alicja, Banks, Rosamonde E, Selby, Peter J, Easton, Douglas F, Pharoah, Paul, Andreotti, Gabriella, Freeman, Laura E Beane, Koutros, Stella, Albanes, Demetrius, Mannisto, Satu, Weinstein, Stephanie, Clark, Peter E, Edwards, Todd E, Lipworth, Loren, Gapstur, Susan M, Stevens, Victoria L, Carol, Hallie, Freedman, Matthew L, Pomerantz, Mark M, Cho, Eunyoung, Kraft, Peter, Preston, Mark A, Wilson, Kathryn M, Gaziano, J Michael, Sesso, Howard S, Black, Amanda, Freedman, Neal D, Huang, Wen-Yi, Anema, John G, Kahnoski, Richard J, Lane, Brian R, Noyes, Sabrina L, Petillo, David, Colli, Leandro M, Sampson, Joshua N, Besse, Celine, Blanche, Helene, Boland, Anne, Burdette, Laurie, Prokhortchouk, Egor, Skryabin, Konstantin G, Yeager, Meredith, Mijuskovic, Mirjana, Ognjanovic, Miodrag, Foretova, Lenka, Holcatova, Ivana, Janout, Vladimir, Mates, Dana, Mukeriya, Anush, Rascu, Stefan, Zaridze, David, Bencko, Vladimir, Cybulski, Cezary, Fabianova, Eleonora, Jinga, Viorel, Lissowska, Jolanta, Lubinski, Jan, Navratilova, Marie, Rudnai, Peter, Szeszenia-Dabrowska, Neonila, Benhamou, Simone, Cancel-Tassin, Geraldine, Cussenot, Olivier, Bueno-de-Mesquita, H B As, Canzian, Federico, Duell, Eric J, Ljungberg, Börje, Sitaram, Raviprakash T, Peters, Ulrike, White, Emily, Anderson, Garnet L, Johnson, Lisa, Luo, Juhua, Buring, Julie, Lee, I-Min, Chow, Wong-Ho, Moore, Lee E, Wood, Christopher, Eisen, Timothy, Larkin, James, Choueiri, Toni K, Lathrop, G Mark, Teh, Bin Tean, Deleuze, Jean-Francois, Wu, Xifeng, Houlston, Richard S, Brennan, Paul, Chanock, Stephen J, Scelo, Ghislaine, and Purdue, Mark P
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- 2018
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45. No association between circulating concentrations of vitamin D and risk of lung cancer : an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)
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Muller, D. C., Hodge, A. M., Fanidi, A., Albanes, D., Mai, X. M., Shu, X. O., Weinstein, S. J., Larose, T. L., Zhang, X., Han, J., Stampfer, M. J., Smith-Warner, S. A., Ma, J., Gaziano, J. M., Sesso, H. D., Stevens, V. L., McCullough, M. L., Layne, T. M., Prentice, R., Pettinger, M., Thomson, C. A., Zheng, W., Gao, Y. T., Rothman, N., Xiang, Y. B., Cai, H., Wang, R., Yuan, J. M., Koh, W. P., Butler, L. M., Cai, Q., Blot, W. J., Wu, J., Ueland, P. M., Midttun, O., Langhammer, A., Hveem, K., Johansson, M., Hultdin, Johan, Grankvist, Kjell, Arslan, A. A., Le Marchand, L., Severi, G., Brennan, P., Muller, D. C., Hodge, A. M., Fanidi, A., Albanes, D., Mai, X. M., Shu, X. O., Weinstein, S. J., Larose, T. L., Zhang, X., Han, J., Stampfer, M. J., Smith-Warner, S. A., Ma, J., Gaziano, J. M., Sesso, H. D., Stevens, V. L., McCullough, M. L., Layne, T. M., Prentice, R., Pettinger, M., Thomson, C. A., Zheng, W., Gao, Y. T., Rothman, N., Xiang, Y. B., Cai, H., Wang, R., Yuan, J. M., Koh, W. P., Butler, L. M., Cai, Q., Blot, W. J., Wu, J., Ueland, P. M., Midttun, O., Langhammer, A., Hveem, K., Johansson, M., Hultdin, Johan, Grankvist, Kjell, Arslan, A. A., Le Marchand, L., Severi, G., and Brennan, P.
- Abstract
Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.
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- 2018
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46. Impaired functional vitamin B6 status is associated with increased risk of lung cancer
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Theofylaktopoulou, Despoina, Midttun, Oivind, Ueland, Per M., Meyer, Klaus, Fanidi, Anouar, Zheng, Wei, Shu, Xiao-Ou, Xiang, Yong-Bing, Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Giles, Graham G., Hodge, Allison, Cai, Qiuyin, Blot, William J., Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L., McCullough, Marjorie M., Weinstein, Stephanie J., Albanes, Demetrius, Ziegler, Regina, Freedman, Neal D., Langhammer, Arnulf, Hveem, Kristian, Naess, Marit, Sesso, Howard D., Gaziano, J. Michael, Buring, Julie E., Lee, I-Min, Severi, Gianluca, Zhang, Xuehong, Stampfer, Meir J., Han, Jiali, Smith-Warner, Stephanie A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Yuan, Jian-Min, Wang, Renwei, Butler, Lesley M., Koh, Woon-Puay, Gao, Yu-Tang, Rothman, Nathaniel, Ericson, Ulrika, Sonestedt, Emily, Visvanathan, Kala, Jones, Miranda R., Relton, Caroline, Brennan, Paul, Johansson, Mattias, Ulvik, Arve, Theofylaktopoulou, Despoina, Midttun, Oivind, Ueland, Per M., Meyer, Klaus, Fanidi, Anouar, Zheng, Wei, Shu, Xiao-Ou, Xiang, Yong-Bing, Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Giles, Graham G., Hodge, Allison, Cai, Qiuyin, Blot, William J., Wu, Jie, Johansson, Mikael, Hultdin, Johan, Grankvist, Kjell, Stevens, Victoria L., McCullough, Marjorie M., Weinstein, Stephanie J., Albanes, Demetrius, Ziegler, Regina, Freedman, Neal D., Langhammer, Arnulf, Hveem, Kristian, Naess, Marit, Sesso, Howard D., Gaziano, J. Michael, Buring, Julie E., Lee, I-Min, Severi, Gianluca, Zhang, Xuehong, Stampfer, Meir J., Han, Jiali, Smith-Warner, Stephanie A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Yuan, Jian-Min, Wang, Renwei, Butler, Lesley M., Koh, Woon-Puay, Gao, Yu-Tang, Rothman, Nathaniel, Ericson, Ulrika, Sonestedt, Emily, Visvanathan, Kala, Jones, Miranda R., Relton, Caroline, Brennan, Paul, Johansson, Mattias, and Ulvik, Arve
- Abstract
Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4th vs. 1st) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.
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- 2018
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47. Circulating cotinine concentrations and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
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Larose, Tricia L., Guida, Florence, Fanidi, Anouar, Langhammer, Arnulf, Kveem, Kristian, Stevens, Victoria L., Jacobs, Eric J., Smith-Warner, Stephanie A., Giovannucci, Edward, Albanes, Demetrius, Weinstein, Stephanie J., Freedman, Neal D., Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Cai, Qiuyin, Wu, Jie, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Wilkens, Lynne R., Haiman, Christopher A., Zhang, Xuehong, Stampfer, Meir J., Hodge, Allison M., Giles, Graham G., Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Wang, Renwei, Yuan, Jian-Min, Gao, Yu-Tang, Koh, Woon-Puay, Shu, Xiao-Ou, Zheng, Wei, Xiang, Yong-Bing, Li, Honglan, Lan, Qing, Visvanathan, Kala, Bolton, Judith Hoffman, Ueland, Per Magne, Midttun, Oivind, Caporaso, Neil, Purdue, Mark, Sesso, Howard D., Buring, Julie E., Lee, I-Min, Gaziano, J. Michael, Manjer, Jonas, Brunnstrom, Hans, Brennan, Paul, Johansson, Mattias, Larose, Tricia L., Guida, Florence, Fanidi, Anouar, Langhammer, Arnulf, Kveem, Kristian, Stevens, Victoria L., Jacobs, Eric J., Smith-Warner, Stephanie A., Giovannucci, Edward, Albanes, Demetrius, Weinstein, Stephanie J., Freedman, Neal D., Prentice, Ross, Pettinger, Mary, Thomson, Cynthia A., Cai, Qiuyin, Wu, Jie, Blot, William J., Arslan, Alan A., Zeleniuch-Jacquotte, Anne, Le Marchand, Loic, Wilkens, Lynne R., Haiman, Christopher A., Zhang, Xuehong, Stampfer, Meir J., Hodge, Allison M., Giles, Graham G., Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Wang, Renwei, Yuan, Jian-Min, Gao, Yu-Tang, Koh, Woon-Puay, Shu, Xiao-Ou, Zheng, Wei, Xiang, Yong-Bing, Li, Honglan, Lan, Qing, Visvanathan, Kala, Bolton, Judith Hoffman, Ueland, Per Magne, Midttun, Oivind, Caporaso, Neil, Purdue, Mark, Sesso, Howard D., Buring, Julie E., Lee, I-Min, Gaziano, J. Michael, Manjer, Jonas, Brunnstrom, Hans, Brennan, Paul, and Johansson, Mattias
- Abstract
Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine—a nicotine metabolite and biomarker of recent tobacco exposure—provides additional information on lung cancer risk. Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis. Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32–1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68–0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64–0.68) (P = 1.5x10–9). Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.
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- 2018
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48. Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)
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Fanidi, Anouar, Muller, David C, Yuan, Jian-Min, Stevens, Victoria L, Weinstein, Stephanie J, Albanes, Demetrius, Prentice, Ross, Thomsen, Cynthia A, Pettinger, Mary, Cai, Qiuyin, Blot, William J, Wu, Jie, Arslan, Alan A, Zeleniuch-Jacquotte, Anne, McCullough, Marjorie L, Le Marchand, Loic, Wilkens, Lynne R, Haiman, Christopher A, Zhang, Xuehong, Han, Jiali, Stampfer, Meir J, Smith-Warner, Stephanie A, Giovannucci, Edward, Giles, Graham G, Hodge, Allison M, Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Langhammer, Arnulf, Krokstad, Steinar, Næss, Marit, Wang, Renwei, Gao, Yu-Tang, Butler, Lesley M, Koh, Woon-Puay, Shu, Xiao-Ou, Xiang, Yong-Bing, Li, Honglan, Zheng, Wei, Lan, Qing, Visvanathan, Kala, Bolton, Judith Hoffman, Ueland, Per Magne, Midttun, Øivind, Ulvik, Arve, Caporaso, Neil E, Purdue, Mark, Ziegler, Regina G, Freedman, Neal D, Buring, Julie E, Lee, I-Min, Sesso, Howard D, Gaziano, J Michael, Manjer, Jonas, Ericson, Ulrika, Relton, Caroline, Brennan, Paul, Johansson, Mattias, Fanidi, Anouar, Muller, David C, Yuan, Jian-Min, Stevens, Victoria L, Weinstein, Stephanie J, Albanes, Demetrius, Prentice, Ross, Thomsen, Cynthia A, Pettinger, Mary, Cai, Qiuyin, Blot, William J, Wu, Jie, Arslan, Alan A, Zeleniuch-Jacquotte, Anne, McCullough, Marjorie L, Le Marchand, Loic, Wilkens, Lynne R, Haiman, Christopher A, Zhang, Xuehong, Han, Jiali, Stampfer, Meir J, Smith-Warner, Stephanie A, Giovannucci, Edward, Giles, Graham G, Hodge, Allison M, Severi, Gianluca, Johansson, Mikael, Grankvist, Kjell, Langhammer, Arnulf, Krokstad, Steinar, Næss, Marit, Wang, Renwei, Gao, Yu-Tang, Butler, Lesley M, Koh, Woon-Puay, Shu, Xiao-Ou, Xiang, Yong-Bing, Li, Honglan, Zheng, Wei, Lan, Qing, Visvanathan, Kala, Bolton, Judith Hoffman, Ueland, Per Magne, Midttun, Øivind, Ulvik, Arve, Caporaso, Neil E, Purdue, Mark, Ziegler, Regina G, Freedman, Neal D, Buring, Julie E, Lee, I-Min, Sesso, Howard D, Gaziano, J Michael, Manjer, Jonas, Ericson, Ulrika, Relton, Caroline, Brennan, Paul, and Johansson, Mattias
- Abstract
Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown. Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models. Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups. Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who av
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- 2018
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49. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
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Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-de-Mesquita, Bas, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, Gaziano, J. Michael M., Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H., Kupcinskas, Juozas, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I. -Min, LeMarchand, Loic, Lu, Lingeng, Malats, Nuria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelnikova-Duchonova, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., Amundadottir, Laufey T., Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-de-Mesquita, Bas, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, Gaziano, J. Michael M., Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H., Kupcinskas, Juozas, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I. -Min, LeMarchand, Loic, Lu, Lingeng, Malats, Nuria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelnikova-Duchonova, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., and Amundadottir, Laufey T.
- Abstract
In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
- Published
- 2018
- Full Text
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50. Impaired functional vitamin B6 status is associated with increased risk of lung cancer
- Author
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Theofylaktopoulou, D, Midttun, O, Ueland, PM, Meyer, K, Fanidi, A, Zheng, W, Shu, X-O, Xiang, Y-B, Prentice, R, Pettinger, M, Thomson, CA, Giles, GG, Hodge, A, Cai, Q, Blot, WJ, Wu, J, Johansson, M, Hultdin, J, Grankvist, K, Stevens, VL, McCullough, MM, Weinstein, SJ, Albanes, D, Ziegler, R, Freedman, ND, Langhammer, A, Hveem, K, Naess, M, Sesso, HD, Gaziano, JM, Buring, JE, Lee, I-M, Severi, G, Zhang, X, Stampfer, MJ, Han, J, Smith-Warner, SA, Zeleniuch-Jacquotte, A, Le Marchand, L, Yuan, J-M, Wang, R, Butler, LM, Koh, W-P, Gao, Y-T, Rothman, N, Ericson, U, Sonestedt, E, Visvanathan, K, Jones, MR, Relton, C, Brennan, P, Ulvik, A, Theofylaktopoulou, D, Midttun, O, Ueland, PM, Meyer, K, Fanidi, A, Zheng, W, Shu, X-O, Xiang, Y-B, Prentice, R, Pettinger, M, Thomson, CA, Giles, GG, Hodge, A, Cai, Q, Blot, WJ, Wu, J, Johansson, M, Hultdin, J, Grankvist, K, Stevens, VL, McCullough, MM, Weinstein, SJ, Albanes, D, Ziegler, R, Freedman, ND, Langhammer, A, Hveem, K, Naess, M, Sesso, HD, Gaziano, JM, Buring, JE, Lee, I-M, Severi, G, Zhang, X, Stampfer, MJ, Han, J, Smith-Warner, SA, Zeleniuch-Jacquotte, A, Le Marchand, L, Yuan, J-M, Wang, R, Butler, LM, Koh, W-P, Gao, Y-T, Rothman, N, Ericson, U, Sonestedt, E, Visvanathan, K, Jones, MR, Relton, C, Brennan, P, and Ulvik, A
- Abstract
Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.
- Published
- 2018
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