1. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes
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van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, Mckeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia H T, Luk, Andrea O Y, Lee, Heung Man, Lim, Cadmon K P, Szeto, Cheuk Chun, Wing Yee, So, Chan, Juliana C N, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, Mcknight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, Ac, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kr, Riihelä, M, Ryysy, L, Laukkanen, Kh, Nyländen, P, Sademies, A, Anderson, S, Asplund, B, Byskata, U, Liedes, P, Kuusela, M, Virkkala, T, Nikkola, A, Ritola, E, Niska, Tm, Saarinen, H, Oukko-Ruponen, Se, Virtanen, T, Lyytinen, Va, Kari, Ph, Simonen, T, Kaprio, Sa, Kärkkäinen, J, Rantaeskola, B, Kääriäinen, Tp, Haaga, J, Pietiläinen, Al, Klemetti, S, Nyandoto, T, Rontu, E, Satuli-Autere, S, Toivonen, Kr, Lansimaki, Hv, Ahonen, R, Ivaska-Suomela, M, Jauhiainen, A, Laine, Mm, Pellonpää, T, Puranen, R, Airas, Ma, Laakso, J, Rautavaara, K, Erola, Rm, Jatkola, E, Lönnblad, Tr, Malm, A, Mäkelä, J, Rautamo, E, Hentunen, P, Lagerstam, J, Feodoroff, M, Gordin, D, Heikkilä, O, Hietala, K, Fagerudd, J, Korolainen, M, Kyllönen, L, Kytö, J, Lindh, S, Pettersson-Fernholm, K, Rosengård-Bärlund, M, Sandelin, A, Thorn, L, Tuomikangas, J, Vesisenaho, T, Wadén, J, Sipilä, V, Kalliomäki, Ft, Koskelainen, J, Nikkanen, R, Savolainen, N, Sulonen, H, Valtonen, E, Norvio, L, Hämäläinen, A, Toivanen, E, Parta, Ja, Pirttiniemi, I, Aranko, S, Ervasti, S, Kauppinen-Mäkelin, R, Kuusisto, A, Leppälä, T, Nikkilä, K, Pekkonen, L, Jokelainen, Ks, Kananen, K, Karjalainen, M, Kemppainen, P, Mankinen, Am, Reponen, A, Sankari, M, Suominen, P, Lappalainen, A, Liimatainen, M, Santaholma, J, Aimolahti, A, Huovinen, E, Ilkka, V, Lehtimäki, M, Pälikkö-Kontinen, E, Vanhanen, A, Koskinen, E, Siitonen, T, Huttunen, E, Ikäheimo, R, Karhapää, P, Kekäläinen, P, Laakso, M, Lakka, T, Lampainen, E, Moilanen, L, Tanskanen, S, Niskanen, L, Tuovinen, U, Vauhkonen, I, Voutilainen, E, Rcw, Ma, Chan, Jcn, Huang, Y, Lan, Hy, Lok, S, Tomlinson, B, Tsui, Skw, Yu, W, Yip, Kyl, Chan, Tf, Fan, X, So, Wy, Szeto, Cc, Tang, N, Luk, Ao, Tian, X, Jiang, G, Tam, Cht, Lee, Hm, Lim, Ckp, Chan, Kkh, Xie, F, Acw, Ng, Cheung, Gpy, Yeung, Mw, Mai, S, Zhang, S, Yu, P, Weng, M, Maxwell, Ap, Mcknight, Aj, Savage, Da, Walker, J, Thomas, S, Viberti, Gc, Boulton, Ajm, Marshall, S, Demaine, Ag, Millward, Ba, Bain, Sc, Sandholm, N, Forsblom, C, Harjutsalo, V, Mäkinen, Vp, Ahola, Aj, Dahlström, E, Lehto, M, Lithovius, R, Panduru, Nm, Parkkonen, M, Saraheimo, M, Söderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, Lm, Tolonen, N, Groop, Ph, Mckay, Gj, Salem, Rm, Isakova, T, Palmer, C, Guiducci, C, Taylor, A, Mirel, Db, Williams, Ww, Hirschhorn, Jn, Florez, Jc, Brennan, Ep, Sadlier, Dm, Martin, F, Godson, C, Mayer, L, Gubitosi-Klug, R, Bourne, P, Schutta, M, Lackaye, Me, Gregory, Ns, Kruger, D, Jones, Jk, Bhan, A, Golden, E, Aiello, L, Larkin, M, Nathan, D, Ziegler, G, Caulder, S, Pittman, C, Luttrell, L, Lopes-Virella, M, Johnson, M, Gunyou, K, Bergenstal, R, Vittetoe, B, Sivitz, W, Flaherty, N, Bantle, J, Hitt, S, Goldstein, D, Hainsworth, D, Cimino, L, Orchard, T, Wigley, C, Dagogo-Jack, S, Strowig, S, Raskin, P, Barnie, A, Zinman, B, Fahlstrom, R, Palmer, J, Harth, J, Driscoll, M, Mcdonald, C, Lipps Hagan, J, May, M, Levandoski, L, White, N, Gatcomb, P, Tamborlane, W, Adelman, D, Colson, S, Molitch, M, Lorenzi, G, Mudaliar, S, Johnsonbaugh, S, Miller, R, Canady, J, Schade, D, Bernal, Ml, Malone, J, Morrison, A, Martin, C, Herman, W, Pop-Busui, R, Cowie, C, Leschek, E, Cleary, P, Lachin, J, Braffett, B, Steffes, M, Arends, V, Blodi, B, Danis, R, Lawrence, D, Wabers, H, Soliman, E, Zhang, Zm, Campbell, C, Hensley, S, Keasler, L, Mark, M, Albertini, M, Boustany, C, Ehlgen, A, Gerl, M, Huber, J, Schölch, C, Zimdahl-Gelling, H, Groop, L, Agardh, E, Ahlqvist, E, Ajanki, T, Al Maghrabi, N, Almgren, P, Apelqvist, J, Bengtsson, E, Berglund, L, Björckbacka, H, Blom-Nilsson, U, Borell, M, Burström, A, Cilio, C, Cinthio, M, Dreja, K, Dunér, P, Engelbertsen, D, Fadista, J, Gomez, M, Goncalves, I, Hedblad, B, Hultgårdh, A, Johansson, Me, Kennbäck, C, Kravic, J, Ladenvall, C, Lernmark, Å, Lindholm, E, Ling, C, Luthman, H, Melander, O, Neptin, M, Nilsson, J, Nilsson, P, Nilsson, T, Nordin, G, Orho-Melander, M, Ottoson-Laakso, E, Persson, A, Persson, M, Persson, Må, Postma, J, Pranter, E, Rattik, S, Sterner, G, Tindberg, L, Wigren, M, Zetterqvist, A, Åkerlund, M, Ostling, G, Kanninen, T, Ahonen-Bishopp, A, Eliasson, A, Herrala, T, Tikka-Kleemola, P, Hamsten, A, Betsholtz, C, Björkholm, A, Foroogh, F, Genové, G, Gertow, K, Gigante, B, He, B, Leander, K, Mcleod, O, Nastase-Mannila, M, Patrakka, J, Silveira, A, Strawbridge, R, Tryggvason, K, Vikström, M, Ohrvik, J, Österholm, Am, Thorand, B, Gieger, C, Grallert, H, Ludwig, T, Nitz, B, Schneider, A, Wang-Sattler, R, Zierer, A, Remuzzi, G, Benigni, A, Donadelli, R, Lesti, Md, Noris, M, Perico, N, Perna, A, Piras, R, Ruggenenti, P, Rurali, E, Dunger, D, Chassin, L, Dalton, N, Deanfield, J, Horsford, J, Rice, C, Rudd, J, Walker, N, Whitehead, K, Wong, M, Colhoun, H, Adams, F, Akbar, T, Belch, J, Deshmukh, H, Dove, F, Ellingford, A, Farran, B, Ferguson, M, Henderson, G, Houston, G, Khan, F, Leese, G, Liu, Y, Livingstone, S, Looker, H, Mccann, M, Mcgurnaghan, S, Morris, A, Newton, D, Pearson, E, Reekie, G, Smith, N, Shore, A, Aizawa, K, Ball, C, Bellenger, N, Casanova, F, Frayling, T, Gates, P, Gooding, K, Hattersley, A, Ling, R, Mawson, D, Shandas, R, Strain, D, Thorn, C, Smith, U, Hammarstedt, A, Häring, H, Pedersen, O, Sesti, G, Fagerholm, E, Toppila, I, Valo, E, Salomaa, V, Havulinna, A, Kristiansson, K, Okamo, P, Peltola, T, Perola, M, Pietilä, A, Ripatti, S, Taimi, M, Ylä-Herttuala, S, Babu, M, Dijkstra, M, Gurzeler, E, Huusko, J, Kholová, I, Merentie, M, Poikolainen, M, Mccarthy, M, Groves, C, Juliusdottir, T, Karpe, F, Lagou, V, Rayner, W, Robertson, N, van Zuydam, N, Cobelli, C, Di Camillo, B, Finotello, F, Sambo, F, Toffolo, G, Trifoglio, E, Bellazzi, R, Barbarini, N, Bucalo, M, Larizza, C, Magni, P, Malovini, A, Marini, S, Mulas, F, Quaglini, S, Sacchi, L, Vitali, F, Ferrannini, E, Boldrini, B, Kozakova, M, Mari, A, Morizzo, C, Mota, L, Natali, A, Palombo, C, Venturi, E, Walker, M, Patrono, C, Pagliaccia, F, Rocca, B, Nuutila, P, Haukkala, J, Knuuti, J, Roivainen, A, Saraste, A, Mckeague, P, Colombo, M, Steckel-Hamann, B, Bokvist, K, Shankar, S, Thomas, M, Gan, Lm, Heinonen, S, Jönsson-Rylander, Ac, Momo, R, Schnecke, V, Unwin, R, Walentinsson, A, Whatling, C, Nogoceke, E, Pacheco, Gd, Formentini, I, Schindler, T, Tortoli, P, Bassi, L, Boni, E, Dallai, A, Guidi, F, Lenge, M, Matera, R, Ramalli, A, Ricci, S, Viti, J, Jablonka, B, Crowther, D, Gassenhuber, J, Hess, S, Hubschle, T, Juretschke, Hp, Rutten, H, Sadowski, T, Wohlfart, P, Brosnan, J, Clerin, V, Fauman, E, Hyde, C, Malarstig, A, Pullen, N, Tilley, M, Tuthill, T, Vangjeli, C, Linda T, Ziemek D., Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ronald C W, Ma, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin N A, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, Mccarthy, Mark, I, Palombo, Carlo, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Nefrologian yksikkö, Department of Medicine, Institute for Molecular Medicine Finland, Tiinamaija Tuomi Research Group, Endokrinologian yksikkö, Per Henrik Groop / Principal Investigator, Leif Groop Research Group, HUS Abdominal Center, HUS Internal Medicine and Rehabilitation, and Lee Kong Chian School of Medicine (LKCMedicine)
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0301 basic medicine ,Male ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,LOCI ,Genome-wide association study ,Type 2 diabetes ,Bioinformatics ,Kidney Failure ,0302 clinical medicine ,Genome-wide analysis ,80 and over ,Diabetic Nephropathies ,Renal Insufficiency ,Chronic ,Genome-wide analysis, Type 2 Diabetes ,Aged, 80 and over ,RISK ,INSULIN-RESISTANCE ,diabetes ,Diabetes ,STAGE RENAL-DISEASE ,Single Nucleotide ,Middle Aged ,Type 2 Diabetes ,SUSCEPTIBILITY GENES ,Adult ,Aged ,Case-Control Studies ,Diabetes Mellitus, Type 2 ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Kidney Failure, Chronic ,Polymorphism, Single Nucleotide ,Renal Insufficiency, Chronic ,OBESITY ,BIOLOGICAL PATHWAYS ,nephropathy ,Medical genetics ,Type 2 ,kidney ,medicine.medical_specialty ,Diabetic Nephropathies/epidemiology ,Settore BIO/14 - FARMACOLOGIA ,Renal Insufficiency, Chronic/complications ,NEPHROPATHY ,SNP ,030209 endocrinology & metabolism ,Nephropathy ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Diabetes mellitus ,Journal Article ,Diabetes Mellitus ,Internal Medicine ,medicine ,Medicine [Science] ,Polymorphism ,Diabetic Kidney Disease ,METAANALYSIS ,Genetic heterogeneity ,business.industry ,Diabetes Mellitus, Type 2/complications ,association ,Case-control study ,nutritional and metabolic diseases ,Kidney Failure, Chronic/complications ,FAT DISTRIBUTION ,medicine.disease ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Microalbuminuria ,genetic ,business - Abstract
Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore)
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