Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline. Journal Article

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Authors: Gorski, M; Jung, B; Li, Y; Matias-Garcia, PR; Wuttke, M; Coassin, S; Thio, CHL; Kleber, ME; Winkler, TW; Wanner, V; Chai, JF; Chu, AY; Cocca, M; Feitosa, MF; Ghasemi, S; Hoppmann, A; Horn, K; Li, M; Nutile, T; Scholz, M; Sieber, KB; Teumer, A; Tin, A; Wang, J; Tayo, BO; Ahluwalia, TS; Almgren, P; Bakker, SJL; Banas, B; Bansal, N; Biggs, ML; Boerwinkle, E; Bottinger, EP; Brenner, H; Carroll, RJ; Chalmers, J; Chee, ML; Cheng, CY; Coresh, J; de Borst, MH; Degenhardt, F; Eckardt, KU; Endlich, K; Franke, A; Freitag-Wolf, S; Gampawar, P; Gansevoort, RT; Ghanbari, M; Gieger, C; Hamet, P; Ho, K; Hofer, E; Holleczek, B; Xian Foo, VH; Hutri-Kähönen, N; Hwang, SJ; Ikram, MA; Josyula, NS; Kähönen, M; Khor, CC; Koenig, W; Kramer, H; Krämer, BK; Kühnel, B; Lange, LA; Lehtimäki, T; Lieb, W; Loos, RJF; Lukas, MA; Lyytikäinen, LP; Meisinger, C; Meitinger, T; Melander, O; Milaneschi, Y; Mishra, PP; Mononen, N; Mychaleckyj, JC; Nadkarni, GN; Nauck, M; Nikus, K; Ning, B; Nolte, IM; O'Donoghue, ML; Orho-Melander, M; Pendergrass, SA; Penninx, BWJH; Preuss, MH; Psaty, BM; Raffield, LM; Raitakari, OT; Rettig, R; Rheinberger, M; Rice, KM; Rosenkranz, AR; Rossing, P; Rotter, JI; Sabanayagam, C; Schmidt, H; Schmidt, R; Schöttker, B; Schulz, CA; Sedaghat, S; Shaffer, CM; Strauch, K; Szymczak, S; Taylor, KD; Tremblay, J; Chaker, L; van der Harst, P; van der Most, PJ; Verweij, N; Völker, U; Waldenberger, M; Wallentin, L; Waterworth, DM; White, HD; Wilson, JG; Wong, TY; Woodward, M; Yang, Q; Yasuda, M; Yerges-Armstrong, LM; Zhang, Y; Snieder, H; Wanner, C; Böger, CA; Köttgen, A; Kronenberg, F; Pattaro, C; Heid, IM
Article Title: Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Journal Title: Kidney international
ISSN: 0085-2538
Publisher: Unknown  
Date Published: 2020