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

• Published in: Kidney international Vol. 99; no. 4; pp. 926 - 939
• Main Authors: Li, Yong, Wuttke, Matthias, Winkler, Thomas W., Chai, Jin-Fang, Chu, Audrey Y., Cocca, Massimiliano, Feitosa, Mary F., Hoppmann, Anselm, Horn, Katrin, Li, Man, Nutile, Teresa, Tin, Adrienne, Tayo, Bamidele O., Bakker, Stephan J.L., Banas, Bernhard, Biggs, Mary L., Bottinger, Erwin P., Brenner, Hermann, Chalmers, John, Chee, Miao-Ling, Degenhardt, Frauke, Eckardt, Kai-Uwe, Ghanbari, Mohsen, Gieger, Christian, Hofer, Edith, Xian Foo, Valencia Hui, Hutri-Kähönen, Nina, Ikram, M. Arfan, Kähönen, Mika, Khor, Chiea-Chuen, Koenig, Wolfgang, Kramer, Holly, Krämer, Bernhard K., Kühnel, Brigitte, Lange, Leslie A., Franke, Lude, van der Harst, Pim, Navis, Gerjan, Snieder, Harold, Swertz, Morris, Wolffenbuttel, Bruce H.R., Wijmenga, Cisca, Abecasis, Goncalo, Baras, Aris, Coppola, Giovanni, Economides, Aris, Lotta, Luca A., Overton, John D., Reid, Jeffrey G., Beechert, Christina, Forsythe, Caitlin, Gu, Zhenhua, Lattari, Michael, Padilla, Maria Sotiropoulos, Toledo, Karina, Pradhan, Manasi, Manoochehri, Kia, Ulloa, Ricardo H., Bai, Xiaodong, Barnard, Leland, Blumenfeld, Andrew, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Maxwell, Evan K., Salerno, William, Mitnaul, Lyndon J., Loos, Ruth J.F., Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Milaneschi, Yuri, Mishra, Pashupati P., Mychaleckyj, Josyf C., Nikus, Kjell, Nolte, Ilja M., O’Donoghue, Michelle L., Pendergrass, Sarah A., Penninx, Brenda W.J.H., Preuss, Michael H., Psaty, Bruce M., Raitakari, Olli T., Rettig, Rainer, Rheinberger, Myriam, Rice, Kenneth M., Rosenkranz, Alexander R., Rossing, Peter, Sedaghat, Sanaz, Taylor, Kent D., Tremblay, Johanne, Völker, Uwe, Wallentin, Lars, Waterworth, Dawn M., White, Harvey D., Wilson, James G., Wong, Tien-Yin, Böger, Carsten A., Köttgen, Anna, Heid, Iris M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: acute kidney injury; AMP-Activated Protein Kinases; Basic Medicine; Creatinine; end-stage kidney disease; Genome-Wide Association Study; Glomerular Filtration Rate - genetics; Humans; Kidney; Medical and Health Sciences; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Protein Disulfide-Isomerases; rapid eGFRcrea decline; United Kingdom; United Kingdom; acute kidney injury; end-stage kidney disease; genome-wide association study; rapid eGFRcrea decline
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1016/j.kint.2020.09.030

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/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 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. [Display omitted]