Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
Sieber Karsten B.; de Borst Martin H.; Yerges-Armstrong Laura M.; Kramer Holly; Hwang Shih-Jen; Tayo Bamidele O.; Nauck Matthias; Böger Carsten A.; Cheng Ching-Yu; Milaneschi Yuri; Nutile Teresa; Waterworth Dawn M.; Chee Miao-Li; Nolte Ilja M.; Josyula Navya Shilpa; Kähönen Mika; Horn Katrin; Kleber Marcus E.; Wang Judy; Boerwinkle Eric; Regeneron Genetics Center: Loos Ruth J.F.; Raffield Laura M.; Lyytikäinen Leo-Pekka; Mishra Pashupati P.; Ghasemi Sahar; Tin Adrienne; Preuss Michael H.; Gorski Mathias; Meitinger Thomas; Tremblay Johanne; Völker Uwe; Carroll Robert J.; Chaker Layal; Feitosa Mary F.; Schmidt Reinhold; White Harvey D.; Wanner Christoph; Wilson James G.; Mononen Nina; Winkler Thomas W.; Li Man; Sabanayagam Charumathi; Heid Iris M.; Holleczek Bernd; Cocca Massimiliano; Bansal Nisha; Wanner Veronika; Bakker Stephan J.L.; Woodward Mark; Thio Chris H.L.; Ning Boting; Penninx Brenda W.J.H.; Rheinberger Myriam; Rosenkranz Alexander R.; Gieger Christian; Psaty Bruce M.; Wuttke Matthias; Zhang Yan; Köttgen Anna; Rotter Jerome I.; Teumer Alexander; Yang Qiong; Pattaro Cristian; Endlich Karlhans; Lehtimäki Terho; Ahluwalia Tarunveer S.; Scholz Markus; Ikram M. Arfan; Chalmers John; Jung Bettina; Koenig Wolfgang; Melander Olle; van der Harst Pim; Rice Kenneth M.; Gansevoort Ron T.; Hoppmann Anselm; Lukas Mary Ann; Matias-Garcia Pamela R.; Sedaghat Sanaz; Orho-Melander Marju; Rettig Rainer; Schöttker Ben; Rossing Peter; Verweij Niek; Yasuda Masayuki; Shaffer Christian M.; Kühnel Brigitte; Chai Jin-Fang; Schulz Christina-Alexandra; Khor Chiea-Chuen; Franke Andre; Coresh Josef; Snieder Harold; Szymczak Silke; Xian Foo Valencia Hui; Wong Tien-Yin; O’Donoghue Michelle L.; Nadkarni Girish N.; Wallentin Lars; Raitakari Olli T.; Gampawar Piyush; Li Yong; Taylor Kent D.; Kronenberg Florian; Banas Bernhard; Hamet Pavel; Degenhardt Frauke; Coassin Stefan; Schmidt Helena; Hofer Edith; Brenner Hermann; Strauch Konstantin; Ghanbari Mohsen; Hutri-Kähönen Nina; Chu Audrey Y.; Lange Leslie A.; Biggs Mary L.; Freitag-Wolf Sandra; Waldenberger Melanie; Mychaleckyj Josyf C.; Pendergrass Sarah A.; Nikus Kjell; Krämer Bernhard K.; Lieb Wolfgang; Lifelines Cohort Study; van der Most Peter J.; Ho Kevin; Eckardt Kai-Uwe; Chee Miao-Ling; Meisinger Christa; Bottinger Erwin P.; Almgren Peter
https://urn.fi/URN:NBN:fi-fe2021042823278
Tiivistelmä
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.
Kokoelmat
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