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Diabetes. 2018 Jul;67(7):1414-1427. doi: 10.2337/db17-0914. Epub 2018 Apr 27.

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.

Collaborators (565)

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, Ma RCW, 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, Ng ACW, Cheung GPY, Yeung MW, Mai S, Xie F, 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, Gordin D, Heikkilä O, Hietala K, Kytö J, Lehto M, Lithovius R, Panduru NM, Parkkonen M, Rosengård-Bärlund M, Saraheimo M, Söderlund J, Soro-Paavonen A, Syreeni A, Thorn LM, Tolonen N, Wadén J, Groop PH, McKnight AJ, McKay GJ, Maxwell AP, 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, Zinman B, Lorenzi G, 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, Palmer C, 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, Groop PH, Fagerholm E, Forsblom C, Harjutsalo V, Parkkonen M, Sandholm N, Tolonen N, 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, Laakso M, Merentie M, Poikolainen M, McCarthy M, Groves C, Juliusdottir T, Karpe F, Lagou V, Morris A, 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, Ziemek D.

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.

PMID:
29703844
PMCID:
PMC6014557
[Available on 2019-07-01]
DOI:
10.2337/db17-0914
[Indexed for MEDLINE]
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