06654nas a2201705 4500008004100000022001400041245009500055210006900150260001600219520183100235100002002066700001802086700001302104700002902117700002102146700002002167700002102187700002202208700002302230700002102253700001902274700001902293700002402312700002102336700001902357700002102376700001702397700001202414700001902426700001902445700002302464700002202487700001802509700001502527700002202542700002802564700001902592700002502611700002002636700001802656700001902674700002102693700002402714700002102738700002302759700001902782700001802801700002002819700002002839700001802859700002402877700002302901700002102924700002202945700001802967700002502985700002103010700002303031700002103054700002203075700001703097700001403114700001703128700002103145700002803166700002603194700002003220700002003240700002703260700002003287700002203307700002103329700001803350700002503368700002103393700002103414700002203435700001903457700002003476700002103496700002803517700002303545700002203568700001903590700002103609700002503630700001803655700002603673700002403699700002003723700001703743700001703760700001903777700002803796700002503824700002603849700002703875700002303902700002003925700002303945700002303968700001903991700002404010700002104034700002904055700001904084700002204103700002804125700002004153700002204173700002004195700003204215700002004247700002604267700002404293700002004317700002004337700002204357700001804379700001504397700002704412700001804439700001704457700002604474700002004500700002404520700002104544700002104565700001904586700001904605700001604624700002104640700003104661700001504692700002004707700002204727700002304749700001904772700002404791700002204815700001804837710002704855710003004882856003604912 2020 eng d a1523-175500aMeta-analysis uncovers genome-wide significant variants for rapid kidney function decline.0 aMetaanalysis uncovers genomewide significant variants for rapid c2020 Oct 303 a
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.
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