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8 results on '"Mantere, T"'

1. Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

Author

Kumpula, T. A. (Timo A.), Koivuluoma, S. (Susanna), Soikkonen, L. (Leila), Vorimo, S. (Sandra), Moilanen, J. (Jukka), Winqvist, R. (Robert), Mantere, T. (Tuomo), Kuismin, O. (Outi), Pylkäs, K. (Katri), Kumpula, T. A. (Timo A.), Koivuluoma, S. (Susanna), Soikkonen, L. (Leila), Vorimo, S. (Sandra), Moilanen, J. (Jukka), Winqvist, R. (Robert), Mantere, T. (Tuomo), Kuismin, O. (Outi), and Pylkäs, K. (Katri)

Abstract

CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.

Published
2023

2. Truncating TINF2 p.Tyr312Ter variant and inherited breast cancer susceptibility

Author

Koivuluoma, S. (Susanna), Vorimo, S. (Sandra), Mattila, T. M. (Tiina M.), Tervasmäki, A. (Anna), Kumpula, T. (Timo), Kuismin, O. (Outi), Winqvist, R. (Robert), Moilanen, J. (Jukka), Mantere, T. (Tuomo), Pylkäs, K. (Katri), Koivuluoma, S. (Susanna), Vorimo, S. (Sandra), Mattila, T. M. (Tiina M.), Tervasmäki, A. (Anna), Kumpula, T. (Timo), Kuismin, O. (Outi), Winqvist, R. (Robert), Moilanen, J. (Jukka), Mantere, T. (Tuomo), and Pylkäs, K. (Katri)

Abstract

TINF2 is a critical subunit of the shelterin complex, which protects and maintains the length of telomeres. Pathogenic missense and truncating TINF2 mutations are causative for dyskeratosis congenita (DC), a rare, dominantly inherited bone marrow failure syndrome characterized by mucocutaneous abnormalities and cancer predisposition. Recent reports indicate that specific TINF2 truncating mutations act as high penetrance cancer predisposition alleles outside DC context, including breast cancer in their tumor spectrum. Here, we have evaluated the role of germline mutations in TINF2 and other shelterin genes in inherited breast cancer susceptibility using exome sequencing data from 98 Northern Finnish breast cancer cases with indication of inherited disease predisposition as a discovery cohort. A single protein truncating variant, TINF2 p.Tyr312Ter, was identified in one of the cases (1/98), and four more carriers were observed in the subsequently genotyped unselected breast cancer cohort (4/1904). None of the carriers were reported to have DC. TINF2 p.Tyr312Ter resulted in stable short form of mRNA transcript, and normal telomere length has been indicated by a recent report. Although recurrent in cases (total of 5/2095), TINF2 p.Tyr312Ter is also present in Finnish population controls (8/12,517), and the observed 4-fold higher frequency in cases falls at most into the range of moderate breast cancer risk alleles (OR 3.74, 95% CI 1.22–11.45, p = 0.029). Current results indicate that not all TINF2 truncating variants are high cancer risk alleles and add further evidence that different TINF2 mutations can have very diverse effects on the disease phenotype.

Published
2023

3. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author

Natarajan, P. (Pradeep), Pampana, A. (Akhil), Graham, S. E. (Sarah E.), Ruotsalainen, S. E. (Sanni E.), Perry, J. A. (James A.), de Vries, P. S. (Paul S.), Broome, J. G. (Jai G.), Pirruccello, J. P. (James P.), Honigbere, M. C. (Michael C.), Aragam, K. (Krishna), Wolford, B. (Brooke), Brody, J. A. (Jennifer A.), Antonacci-Fulton, L. (Lucinda), Arden, M. (Moscati), Aslibekyan, S. (Stella), Assimes, T. L. (Themistocles L.), Ballantyne, C. M. (Christie M.), Bielak, L. F. (Lawrence F.), Bisl, J. C. (Joshua C.), Cade, B. E. (Brian E.), Do, R. (Ron), Doddapaneni, H. (Harsha), Emery, L. S. (Leslie S.), Hung, Y.-J. (Yi-Jen), Irvin, M. R. (Marguerite R.), Khan, A. T. (Alyna T.), Lange, L. (Leslie), Lee, J. (Jiwon), Lemaitre, R. N. (Rozenn N.), Martin, L. W. (Lisa W.), Metcalf, G. (Ginger), Montasser, M. E. (May E.), Moon, J.-Y. (Jee-Young), Muzny, D. (Donna), Connell, J. R. (Jeffrey R. O.), Palmer, N. D. (Nicholette D.), Peralta, J. M. (Juan M.), Peyser, P. A. (Patricia A.), Stilp, A. M. (Adrienne M.), Tsai, M. (Michael), Wang, F. F. (Fei Fei), Weeks, D. E. (Daniel E.), Yanek, L. R. (Lisa R.), Wilson, J. G. (James G.), Abecasis, G. (Goncalo), Arnett, D. K. (Donna K.), Becker, L. C. (Lewis C.), Blangercy, J. (John), Boerwinkle, E. (Eric), Bowden, D. W. (Donald W.), Chang, Y.-C. (Yi-Cheng), Chen, Y. I. (Yii-Der, I), Choi, W. J. (Won Jung), Correa, A. (Adolfo), Curran, J. E. (Joanne E.), Daly, M. J. (Mark J.), DutcherE, S. K. (Susan K.), Ellinor, P. T. (Patrick T.), Fornage, M. (Myriam), Freedman, B. I. (Barry, I), Gabriel, S. (Stacey), Germer, S. (Soren), Gibbs, R. A. (Richard A.), He, J. (Jiang), Hveem, K. (Kristian), Jarvik, G. P. (Gail P.), Kaplan, R. C. (Robert C.), Kardia, S. L. (Sharon L. R.), Kennyn, E. (Eimear), Kim, R. W. (Ryan W.), Kooperberg, C. (Charles), Laurie, C. C. (Cathy C.), Lee, S. (Seonwook), Lloyd-Jones, D. M. (Don M.), Loos, R. J. (Ruth J. F.), Lubitz, S. A. (Steven A.), Mathias, R. A. (Rasika A.), Martinez, K. A. (Karine A. Viaud), McGarvey, S. T. (Stephen T.), Mitche, B. D. (Braxton D.), Nickerson, D. A. (Deborah A.), North, K. E. (Kari E.), Palotie, A. (Aarno), Park, C. J. (Cheol Joo), Psat, B. M. (Bruce M. Y.), Rao, D. C. (D. C.), Redline, S. (Susan), Reiner, A. P. (Alexander P.), Seo, D. (Daekwan), Seo, J.-S. (Jeong-Sun), Smith, A. V. (Albert, V), Tracy, R. P. (Russell P.), Kathiresan, S. (Sekar), Cupples, L. A. (L. Adrienne), Rotten, J. I. (Jerome, I), Morrison, A. C. (Alanna C.), Rich, S. S. (Stephen S.), Ripatti, S. (Samuli), Wilier, C. (Cristen), Peloso, G. M. (Gina M.), Vasan, R. S. (Ramachandran S.), Abe, N. (Namiko), Albert, C. (Christine), Almasy, L. (Laura), Alonso, A. (Alvaro), Ament, S. (Seth), Anderson, P. (Peter), Applebaum-Bowden, D. (Deborah), Arking, D. (Dan), Ashley-Koch, A. (Allison), Auer, P. (Paul), Avramopoulos, D. (Dimitrios), Barnard, J. (John), Barnes, K. (Kathleen), Barr, R. G. (R. Graham), Barron-Casella, E. (Emily), Beaty, T. (Terri), Becker, D. (Diane), Beer, R. (Rebecca), Begum, F. (Ferdouse), Beitelshees, A. (Amber), Benjamin, E. (Emelia), Bezerra, M. (Marcos), Bielak, L. (Larry), Blackwel, T. (Thomas), Bowler, R. (Russell), Broecke, U. (Ulrich), Bunting, K. (Karen), Burchard, E. (Esteban), Buth, E. (Erin), Cardwel, J. (Jonathan), Carty, C. (Cara), Casaburi, R. (Richard), Casella, J. (James), Chaffin, M. (Mark), Chang, C. (Christy), Chasman, D. (Daniel), Chavan, S. (Sameer), Chen, B.-J. (Bo-Juen), Chen, W.-M. (Wei-Min), Chol, M. (Michael), Choi, S. H. (Seung Hoan), Chuang, L.-M. (Lee-Ming), Chung, M. (Mina), Conomos, M. P. (Matthew P.), Cornell, E. (Elaine), Crapo, J. (James), Curtis, J. (Jeffrey), Custer, B. (Brian), Damcott, C. (Coleen), Darbar, D. (Dawood), Das, S. (Sayantan), David, S. (Sean), Davis, C. (Colleen), Daya, M. (Michelle), de Andrade, M. (Mariza), DeBaunuo, M. (Michael), Duan, Q. (Qing), Devine, R. D. (Ranjan Deka Dawn DeMeo Scott), Duggirala, Q. R. (Qing Ravi), Durda, J. P. (Jon Peter), Dutcher, S. (Susan), Eaton, C. (Charles), Ekunwe, L. (Lynette), Farber, C. (Charles), Farnaml, L. (Leanna), Fingerlin, T. (Tasha), Flickinger, M. (Matthew), Franceschini, N. (Nora), Fu, M. (Mao), Fullerton, S. M. (Stephanie M.), Fulton, L. (Lucinda), Gan, W. (Weiniu), Gao, Y. (Yan), Gass, M. (Margery), Ge, B. (Bruce), Geng, X. P. (Xiaoqi Priscilla), Gignoux, C. (Chris), Gladwin, M. (Mark), Glahn, D. (David), Gogarten, S. (Stephanie), Gong, D.-W. (Da-Wei), Goring, H. (Harald), Gu, C. C. (C. Charles), Guan, Y. (Yue), Guo, X. (Xiuqing), Haessler, J. (Jeff), Hall, M. (Michael), Harris, D. (Daniel), Hawle, N. Y. (Nicola Y.), Heavner, B. (Ben), Heckbert, S. (Susan), Hernandez, R. (Ryan), Herrington, D. (David), Hersh, C. (Craig), Hidalgo, B. (Bertha), Hixson, J. (James), Hokanson, J. (John), Hong, E. (Elliott), Hoth, K. (Karin), Hsiung, C. A. (Chao Agnes), Huston, H. (Haley), Hwu, C. M. (Chii Min), Jackson, R. (Rebecca), Jain, D. (Deepti), Jaquish, C. (Cashell), Jhun, M. A. (Min A.), Johnsen, J. (Jill), Johnson, A. (Andrew), Johnson, C. (Craig), Johnston, R. (Rich), Jones, K. (Kimberly), Kang, H. M. (Hyun Min), Kaufman, L. (Laura), Kell, S. Y. (Shannon Y.), Kessler, M. (Michael), Kinney, G. (Greg), Konkle, B. (Barbara), Kramer, H. (Holly), Krauter, S. (Stephanie), Lange, C. (Christoph), Lange, E. (Ethan), Laurie, C. (Cecelia), LeBoff, M. (Meryl), Lee, S. S. (Seunggeun Shawn), Lee, W.-J. (Wen-Jane), LeFaive, J. (Jonathon), Levine, D. (David), Levy, D. (Dan), Lewis, J. (Joshua), Li, Y. (Yun), Lin, H. (Honghuang), Lin, K. H. (Keng Han), Lin, X. (Xihong), Liu, S. (Simin), Liu, Y. (Yongmei), Lunetta, K. (Kathryn), Luo, J. (James), Mahaney, M. (Michael), Make, B. (Barry), Manichaikul, A. (Ani), Mansonl, J. (JoAnn), Margolin, L. (Lauren), Mathai, S. (Susan), McArdle, P. (Patrick), Mcdonald, M.-L. (Merry-Lynn), McFarland, S. (Sean), McHugh, C. (Caitlin), Mei, H. (Hao), Meyers, D. A. (Deborah A.), Mikulla, J. (Julie), Min, N. (Nancy), Minear, M. (Mollie), Minster, R. L. (Ryan L.), Musani, S. (Solomon), Mwasongwe, S. (Stanford), Mychaleckyj, J. C. (Josyf C.), Nadkarni, G. (Girish), Naik, R. (Rakhi), Naseri, T. (Take), Nekhai, S. (Sergei), Nelson, S. C. (Sarah C.), Nickerson, D. (Deborah), Connell, J. O. (Jeff O.), Connor, T. O. (Tim O.), Ochs-Balcom, H. (Heather), Pankow, J. (James), Papanicolaou, G. (George), Parkerl, M. (Margaret), Parsa, A. (Afshin), Penchey, S. (Sara), Perez, M. (Marco), Peters, U. (Ulrike), Phillips, L. S. (Lawrence S.), Phillips, S. (Sam), Pollin, T. (Toni), Post, W. (Wendy), Becker, J. P. (Julia Powers), Boorgula, M. P. (Meher Preethi), Preuss, M. (Michael), Prokopenko, D. (Dmitry), Qasba, P. (Pankaj), Qiao, D. (Dandi), Rafaels, N. (Nicholas), Raffield, L. (Laura), Rasmussen-Torvik, L. (Laura), Ratan, A. (Aakrosh), Reed, R. (Robert), Reganl, E. (Elizabeth), Reupena, M. S. (Muagututi Sefuiva), Rice, K. (Ken), Roden, D. (Dan), Roselli, C. (Carolina), Ruczinski, I. (Ingo), Russel, P. (Pamela), Ruuska, S. (Sarah), Ryan, K. (Kathleen), Sabino, E. C. (Ester Cerdeira), Sakornsakolpatl, P. (Phuwanat), Salzberg, S. (Steven), Sandow, K. (Kevin), Sankaran, V. G. (Vijay G.), Scheller, C. (Christopher), Schmidt, E. (Ellen), Schwander, K. (Karen), Schwartz, D. (David), Sciurba, F. (Frank), Seidman, C. (Christine), Seidman, J. (Jonathan), Sheehan, V. (Vivien), Shetty, A. (Amol), Shetty, A. (Aniket), Sheu, W. H. (Wayne Hui-Heng), Shoemaker, M. B. (M. Benjamin), Silver, B. (Brian), Silvermanl, E. (Edwin), Smith, J. (Jennifer), Smith, J. (Josh), Smith, N. (Nicholas), Smith, T. (Tanja), Smoller, S. (Sylvia), Snively, B. (Beverly), Soferlm, T. (Tamar), Streeten, E. (Elizabeth), Su, J. L. (Jessica Lasky), Sung, Y. J. (Yun Ju), Sylvia, J. (Jody), Sztalryd, C. (Carole), Taliun, D. (Daniel), Tang, H. (Hua), Taub, M. (Margaret), Taylor, K. D. (Kent D.), Taylor, S. (Simeon), Telen, M. (Marilyn), Thornton, T. A. (Timothy A.), Tinker, L. (Lesley), Tirschwel, D. (David), Tiwari, H. (Hemant), Vaidya, D. (Dhananjay), VandeHaar, P. (Peter), Vrieze, S. (Scott), Walker, T. (Tarik), Wallace, R. (Robert), Waits, A. (Avram), Wan, E. (Emily), Wang, H. (Heming), Watson, K. (Karol), Weir, B. (Bruce), Weiss, S. (Scott), Weng, L.-C. (Lu-Chen), Williams, K. (Kayleen), Williams, L. K. (L. Keoki), Wilson, C. (Carla), Wong, Q. (Quenna), Xu, H. (Huichun), Yang, I. (Ivana), Yang, R. (Rongze), Zaghlou, N. (Norann), Zekavat, M. (Maryam), Zhang, Y. (Yingze), Zhao, S. X. (Snow Xueyan), Zhao, W. (Wei), Zni, D. (Degui), Zhou, X. (Xiang), Zhu, X. (Xiaofeng), Zody, M. (Michael), Zoellner, S. (Sebastian), Daly, M. (Mark), Jacob, H. (Howard), Matakidou, A. (Athena), Runz, H. (Heiko), John, S. (Sally), Plenge, R. (Robert), McCarthy, M. (Mark), Hunkapiller, J. (Julie), Ehm, M. (Meg), Waterworth, D. (Dawn), Fox, C. (Caroline), Malarstig, A. (Anders), Klinger, K. (Kathy), Call, K. (Kathy), Mkel, T. (Tomi), Kaprio, J. (Jaakko), Virolainen, P. (Petri), Pulkki, K. (Kari), Kilpi, T. (Terhi), Perola, M. (Markus), Partanen, J. (Jukka), Pitkranta, A. (Anne), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Savinainen, K. (Kimmo), Kosma, V.-M. (Veli-Matti), Kujala, U. (Urho), Tuovila, O. (Outi), Hendolin, M. (Minna), Pakkanen, R. (Raimo), Waring, J. (Jeff), Riley-Gillis, B. (Bridget), Liu, J. (Jimmy), Biswas, S. (Shameek), Diogo, D. (Dorothee), Marshall, C. (Catherine), Hu, X. (Xinli), Gossel, M. (Matthias), Schleutker, J. (Johanna), Arvas, M. (Mikko), Hinttala, R. (Reetta), Kettunen, J. (Johannes), Laaksonen, R. (Reijo), Mannermaa, A. (Arto), Paloneva, J. (Juha), Soininen, H. (Hilkka), Julkunen, V. (Valtteri), Remes, A. (Anne), Klviinen, R. (Reetta), Hiltunen, M. (Mikko), Peltola, J. (Jukka), Tienari, P. (Pentti), Rinne, J. (Juha), Ziemann, A. (Adam), Waring, J. (Jeffrey), Esmaeeli, S. (Sahar), Smaoui, N. (Nizar), Lehtonen, A. (Anne), Eaton, S. (Susan), Landenper, S. (Sanni), Michon, J. (John), Kerchner, G. (Geoff), Bowers, N. (Natalie), Teng, E. (Edmond), Eicher, J. (John), Mehta, V. (Vinay), Gormle, P. Y. (Padhraig Y.), Linden, K. (Kari), Whelan, C. (Christopher), Xu, F. (Fanli), Pulford, D. (David), Frkkil, M. (Martti), Pikkarainen, S. (Sampsa), Jussila, A. (Airi), Blomster, T. (Timo), Kiviniemi, M. (Mikko), Voutilainen, M. (Markku), Georgantas, B. (Bob), Heap, G. (Graham), Rahimov, F. (Fedik), Usiskin, K. (Keith), Maranville, J. (Joseph), Lu, T. (Tim), Oh, D. (Danny), Kalpala, K. (Kirsi), Miller, M. (Melissa), McCarthy, L. (Linda), Eklund, K. (Kari), Palomki, A. (Antti), Isomki, P. (Pia), Piri, L. (Laura), Kaipiainen-Seppnen, O. (Oili), Lertratanaku, A. (Apinya), Bing, D. C. (David Close Marla Hochfeld Nan), Gordillo, J. E. (Jorge Esparza), Mars, N. (Nina), Laitinen, T. (Tarja), Pelkonen, M. (Margit), Kauppi, P. (Paula), Kankaanranta, H. (Hannu), Harju, T. (Terttu), Greenberg, S. (Steven), Chen, H. (Hubert), Betts, J. (Jo), Ghosh, S. (Soumitra), Salomaa, V. (Veikko), Niiranen, T. (Teemu), Juonala, M. (Markus), Metsrinne, K. (Kaj), Khnen, M. (Mika), Junttila, J. (Juhani), Laakso, M. (Markku), Pihlajamki, J. (Jussi), Sinisalo, J. (Juha), Taskinen, M.-R. (Marja-Riitta), Tuomi, T. (Tiinamaija), Laukkanen, J. (Jari), Challis, B. (Ben), Peterson, A. (Andrew), Chu, A. (Audrey), Parkkinen, J. (Jaakko), Muslin, A. (Anthony), Joensuu, H. (Heikki), Meretoja, T. (Tuomo), Aaltonen, L. (Lauri), Auranen, A. (Annika), Karihtala, P. (Peeter), Kauppila, S. (Saila), Auvinen, P. (Pivi), Elenius, K. (Klaus), Popovic, R. (Relja), Schutzman, J. (Jennifer), Loboda, A. (Andrey), Chhibber, A. (Aparna), Lehtonen, H. (Heli), McDonough, S. (Stefan), Crohns, M. (Marika), Kulkarni, D. (Diptee), Kaarniranta, K. (Kai), Turunen, J. (Joni), Ollila, T. (Terhi), Seitsonen, S. (Sanna), Uusitalo, H. (Hannu), Aaltonen, V. (Vesa), Uusitalo-Jrvinen, H. (Hannele), Luodonp, M. (Marja), Hautala, N. (Nina), Strauss, E. (Erich), Chen, H. (Hao), Podgornaia, A. (Anna), Hoffman, J. (Joshua), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Hannula-Jouppi, K. (Katariina), Salmi, T. (Teea), Peltonen, S. (Sirkku), Koulu, L. (Leena), Harvima, I. (Ilkka), Wu, Y. (Ying), Choy, D. (David), Jalanko, A. (Anu), Kajanne, R. (Risto), Lyhs, U. (Ulrike), Kaunisto, M. (Mari), Davis, J. W. (Justin Wade), Quarless, D. (Danjuma), Petrovski, S. (Slav), Chen, C.-Y. (Chia-Yen), Bronson, P. (Paola), Yang, R. (Robert), Chang, D. (Diana), Bhangale, T. (Tushar), Holzinger, E. (Emily), Wang, X. (Xulong), Chen, X. (Xing), Auro, K. (Kirsi), Wang, C. (Clarence), Xu, E. (Ethan), Auge, F. (Franck), Chatelain, C. (Clement), Kurki, M. (Mitja), Karjalainen, J. (Juha), Havulinna, A. (Aki), Palin, K. (Kimmo), Palta, P. (Priit), Parolo, P. D. (Pietro Della Briotta), Zhou, W. (Wei), Lemmel, S. (Susanna), Rivas, M. (Manuel), Harju, J. (Jarmo), Lehisto, A. (Arto), Ganna, A. (Andrea), Llorens, V. (Vincent), Karlsson, A. (Antti), Kristiansson, K. (Kati), Hyvrinen, K. (Kati), Ritari, J. (Jarmo), Wahlfors, T. (Tiina), Koskinen, M. (Miika), Pylkäs, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Mantere, T. (Tuomo), Kangasniemi, E. (Eeva), Heikkinen, S. (Sami), Laakkonen, E. (Eija), Kononen, J. (Juha), Loukola, A. (Anu), Laiho, P. (Pivi), Sistonen, T. (Tuuli), Kaiharju, E. (Essi), Laukkanen, M. (Markku), Jrvensivu, E. (Elina), Lhteenmki, S. (Sini), Mnnikk, L. (Lotta), Wong, R. (Regis), Mattsson, H. (Hannele), Hiekkalinna, T. (Tero), Jimnez, M. G. (Manuel Gonzlez), Donner, K. (Kati), Prn, K. (KaIle), Nunez-Fontarnau, J. (Javier), Kilpelinen, E. (Elina), Sipi, T. P. (Timo P.), Brein, G. (Georg), Dada, A. (Alexander), Awaisa, G. (Ghazal), Shcherban, A. (Anastasia), Sipil, T. (Tuomas), Laivuori, H. (Hannele), Kiiskinen, T. (Tuomo), Siirtola, H. (Harri), Tabuenca, J. G. (Javier Gracia), Kallio, L. (Lila), Soini, S. (Sirpa), Pitknen, K. (Kimmo), and Kuopio, T. (Teijo)

Subjects
Cardiovascular genetics, Genome-wide association studies
Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Published
2021

4. Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

Author

Smits, J. J. (Jeroen J.), de Bruijn, S. E. (Suzanne E.), Lanting, C. P. (Cornelis P.), Oostrik, J. (Jaap), O’Gorman, L. (Luke), Mantere, T. (Tuomo), D. C. (DOOFNL Consortium), Cremers, F. P. (Frans P. M.), Roosing, S. (Susanne), Yntema, H. G. (Helger G.), de Vrieze, E. (Erik), Derks, R. (Ronny), Hoischen, A. (Alexander), Pegge, S. A. (Sjoert A. H.), Neveling, K. (Kornelia), Pennings, R. J. (Ronald J. E.), Kremer, H. (Hannie), Smits, J. J. (Jeroen J.), de Bruijn, S. E. (Suzanne E.), Lanting, C. P. (Cornelis P.), Oostrik, J. (Jaap), O’Gorman, L. (Luke), Mantere, T. (Tuomo), D. C. (DOOFNL Consortium), Cremers, F. P. (Frans P. M.), Roosing, S. (Susanne), Yntema, H. G. (Helger G.), de Vrieze, E. (Erik), Derks, R. (Ronny), Hoischen, A. (Alexander), Pegge, S. A. (Sjoert A. H.), Neveling, K. (Kornelia), Pennings, R. J. (Ronald J. E.), and Kremer, H. (Hannie)

Abstract

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Published
2021

5. Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Author

Tabassum, R. (Rubina), Ramo, J. T. (Joel T.), Ripatti, P. (Pietari), Koskela, J. T. (Jukka T.), Kurki, M. (Mitja), Karjalainen, J. (Juha), Palta, P. (Priit), Hassan, S. (Shabbeer), Nunez-Fontarnau, J. (Javier), Kiiskinen, T. T. (Tuomo T. J.), Soderlund, S. (Sanni), Matikainen, N. (Niina), Gerl, M. J. (Mathias J.), Surma, M. A. (Michal A.), Klose, C. (Christian), Stitziel, N. O. (Nathan O.), Laivuori, H. (Hannele), Havulinna, A. S. (Aki S.), Service, S. K. (Susan K.), Salomaa, V. (Veikko), Pirinen, M. (Matti), Jauhiainen, M. (Matti), Daly, M. J. (Mark J.), Freimer, N. B. (Nelson B.), Palotie, A. (Aarno), Taskinen, M.-R. (Marja-Riitta), Simons, K. (Kai), Ripatti, S. (Samuli), Jalanko, A. (Anu), Kaprio, J. (Jaakko), Donner, K. (Kati), Kaunisto, M. (Mari), Mars, N. (Nina), Dada, A. (Alexander), Shcherban, A. (Anastasia), Ganna, A. (Andrea), Lehisto, A. (Arto), Kilpelainen, E. (Elina), Brein, G. (Georg), Awaisa, G. (Ghazal), Harju, J. (Jarmo), Parr, K. (Kalle), Parolo, P. D. (Pietro Della Briotta), Kajanne, R. (Risto), Lemmela, S. (Susanna), Sipila, T. P. (Timo P.), Sipila, T. (Tuomas), Lyhs, U. (Ulrike), Llorens, V. (Vincent), Niiranen, T. (Teemu), Kristiansson, K. (Kati), Mannikko, L. (Lotta), Jimenez, M. G. (Manuel Gonzalez), Perola, M. (Markus), Wong, R. (Regis), Kilpi, T. (Terhi), Hiekkalinna, T. (Tero), Jarvensivu, E. (Elina), Kaiharju, E. (Essi), Mattsson, H. (Hannele), Laukkanen, M. (Markku), Laiho, P. (Paivi), Lahteenmaki, S. (Sini), Sistonen, T. (Tuuli), Soini, S. (Sirpa), Ziemann, A. (Adam), Lehtonen, A. (Anne), Lertratanakul, A. (Apinya), Georgantas, B. (Bob), Riley-Gillis, B. (Bridget), Quarless, D. (Danjuma), Rahimov, F. (Fedik), Heap, G. (Graham), Jacob, H. (Howard), Waring, J. (Jeffrey), Davis, J. W. (Justin Wade), Smaoui, N. (Nizar), Popovic, R. (Relja), Esmaeeli, S. (Sahar), Waring, J. (Jeff), Matakidou, A. (Athena), Challis, B. (Ben), Close, D. (David), Petrovski, S. (Slave), Karlsson, A. (Antti), Schleutker, J. (Johanna), Pulkki, K. (Kari), Virolainen, P. (Petri), Kallio, L. (Lila), Mannermaa, A. (Arto), Heikkinen, S. (Sami), Kosma, V.-M. (Veli-Matti), Chen, C.-Y. (Chia-Yen), Runz, H. (Heiko), Liu, J. (Jimmy), Bronson, P. (Paola), John, S. (Sally), Landenpera, S. (Sanni), Eaton, S. (Susan), Zhou, W. (Wei), Hendolin, M. (Minna), Tuovila, O. (Outi), Pakkanen, R. (Raimo), Maranville, J. (Joseph), Usiskin, K. (Keith), Hochfeld, M. (Marla), Plenge, R. (Robert), Yang, R. (Robert), Biswas, S. (Shameek), Greenberg, S. (Steven), Laakkonen, E. (Eija), Kononen, J. (Juha), Paloneva, J. (Juha), Kujala, U. (Urho), Kuopio, T. (Teijo), Laukkanen, J. (Jari), Kangasniemi, E. (Eeva), Savinainen, K. (Kimmo), Laaksonen, R. (Reijo), Arvas, M. (Mikko), Ritari, J. (Jarmo), Partanen, J. (Jukka), Hyvarinen, K. (Kati), Wahlfors, T. (Tiina), Peterson, A. (Andrew), Oh, D. (Danny), Chang, D. (Diana), Teng, E. (Edmond), Strauss, E. (Erich), Kerchner, G. (Geoff), Chen, H. (Hao), Chen, H. (Hubert), Schutzman, J. (Jennifer), Michon, J. (John), Hunkapiller, J. (Julie), McCarthy, M. (Mark), Bowers, N. (Natalie), Lu, T. (Tim), Bhangale, T. (Tushar), Pulford, D. (David), Waterworth, D. (Dawn), Kulkarni, D. (Diptee), Xu, F. (Fanli), Betts, J. (Jo), Gordillo, J. E. (Jorge Esparza), Hoffman, J. (Joshua), Auro, K. (Kirsi), McCarthy, L. (Linda), Ghosh, S. (Soumitra), Ehm, M. (Meg), Pitkanen, K. (Kimmo), Makela, T. (Tomi), Loukola, A. (Anu), Joensuu, H. (Heikki), Sinisalo, J. (Juha), Eklund, K. (Kari), Aaltonen, L. (Lauri), Farkkila, M. (Martti), Carpen, O. (Olli), Kauppi, P. (Paula), Tienari, P. (Pentti), Ollila, T. (Terhi), Tuomi, T. (Tiinamaija), Meretoja, T. (Tuomo), Pitkaranta, A. (Anne), Turunen, J. (Joni), Hannula-Jouppi, K. (Katariina), Pikkarainen, S. (Sampsa), Seitsonen, S. (Sanna), Koskinen, M. (Miika), Palomaki, A. (Antti), Rinne, J. (Juha), Metsarinne, K. (Kaj), Elenius, K. (Klaus), Pirila, L. (Laura), Koulu, L. (Leena), Voutilainen, M. (Markku), Juonala, M. (Markus), Peltonen, S. (Sirkku), Aaltonen, V. (Vesa), Loboda, A. (Andrey), Podgornaia, A. (Anna), Chhibber, A. (Aparna), Chu, A. (Audrey), Fox, C. (Caroline), Diogo, D. (Dorothee), Holzinger, E. (Emily), Eicher, J. (John), Gormley, P. (Padhraig), Mehta, V. (Vinay), Wang, X. (Xulong), Kettunen, J. (Johannes), Pylkas, K. (Katri), Kalaoja, M. (Marita), Karjalainen, M. (Minna), Hinttala, R. (Reetta), Kaarteenaho, R. (Riitta), Vainio, S. (Seppo), Mantere, T. (Tuomo), Remes, A. (Anne), Huhtakangas, J. (Johanna), Junttila, J. (Juhani), Tasanen, K. (Kaisa), Huilaja, L. (Laura), Luodonpaa, M. (Marja), Hautala, N. (Nina), Karihtala, P. (Peeter), Kauppila, S. (Saila), Harju, T. (Terttu), Blomster, T. (Timo), Soininen, H. (Hilkka), Harvima, I. (Ilkka), Pihlajamaki, J. (Jussi), Kaarniranta, K. (Kai), Pelkonen, M. (Margit), Laakso, M. (Markku), Hiltunen, M. (Mikko), Kiviniemi, M. (Mikko), Kaipiainen-Seppanen, O. (Oili), Auvinen, P. (Paivi), Kalviainen, R. (Reetta), Julkunen, V. (Valtteri), Malarstig, A. (Anders), Hedman, A. (Asa), Marshal, C. (Catherine), Whelan, C. (Christopher), Lehtonen, H. (Heli), Parkkinen, J. (Jaakko), Linden, K. (Kari), Kalpala, K. (Kirsi), Miller, M. (Melissa), Bing, N. (Nan), McDonough, S. (Stefan), Chen, X. (Xing), Hu, X. (Xinli), Wu, Y. (Ying), Auranen, A. (Annika), Jussila, A. (Airi), Uusitalo-Jarvinen, H. (Hannele), Kankaanranta, H. (Hannu), Uusitalo, H. (Hannu), Peltola, J. (Jukka), Kahonen, M. (Mika), Isomaki, P. (Pia), Laitinen, T. (Tarja), Salmi, T. (Teea), Muslin, A. (Anthony), Wang, C. (Clarence), Chatelain, C. (Clement), Xu, E. (Ethan), Auge, F. (Franck), Call, K. (Kathy), Klinger, K. (Kathy), Crohns, M. (Marika), Gossel, M. (Matthias), Palin, K. (Kimmo), Rivas, M. (Manuel), Siirtola, H. (Harri), and Tabuenca, J. G. (Javier Gracia)

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P

Published
2019

6. FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population

Author

Kiiski, J. I. (Johanna I.), Tervasmäki, A. (Anna), Pelttari, L. M. (Liisa M.), Khan, S. (Sofia), Mantere, T. (Tuomo), Pylkäs, K. (Katri), Mannermaa, A. (Arto), Tengström, M. (Maria), Kvist, A. (Anders), Borg, Å. (Åke), Kosma, V.-M. (Veli-Matti), Kallioniemi, A. (Anne), Schleutker, J. (Johanna), Bützow, R. (Ralf), Blomqvist, C. (Carl), Aittomäki, K. (Kristiina), Winqvist, R. (Robert), Nevanlinna, H. (Heli), Kiiski, J. I. (Johanna I.), Tervasmäki, A. (Anna), Pelttari, L. M. (Liisa M.), Khan, S. (Sofia), Mantere, T. (Tuomo), Pylkäs, K. (Katri), Mannermaa, A. (Arto), Tengström, M. (Maria), Kvist, A. (Anders), Borg, Å. (Åke), Kosma, V.-M. (Veli-Matti), Kallioniemi, A. (Anne), Schleutker, J. (Johanna), Bützow, R. (Ralf), Blomqvist, C. (Carl), Aittomäki, K. (Kristiina), Winqvist, R. (Robert), and Nevanlinna, H. (Heli)

Abstract

Purpose: The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. Methods: We genotyped the FANCM c.5791C>mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. Results: The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87–4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65–16.0, P = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32–2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77–5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. Conclusions: These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.

Published
2017

7. Dopamine D2/D3-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics.

Author

Tupala, E., Hall, H., Bergström, K., Särkioja, T., Räsänen, P., Mantere, T., Callaway, J., Hiltunen, J., and Tiihonen, J.

Subjects
ALCOHOLISM, DOPAMINE receptors, NUCLEUS accumbens, AMYGDALOID body
Abstract

Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. We evaluated the densities of DA D[sub 2]/D[sub 3] receptors and transporters in the nucleus accumbens and amygdala of post-mortem human brains by using [[sup 125]I]epidepride and [[sup 125]I]PE21 as radioligands in whole hemispheric autoradiography of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean binding of [[sup 125]I]epidepride to DA D[sub 2]/D[sub 3] receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and [[sup 125]I]PE21 binding to DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. Our results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function. [ABSTRACT FROM AUTHOR]

Published
2001
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