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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Alexander TeumerYong LiSahar GhasemiBram P PrinsMatthias WuttkeTobias HermleAyush GiriKarsten B SieberChengxiang QiuHolger KirstenAdrienne TinAudrey Y ChuNisha BansalMary F FeitosaLihua WangJin Fang ChaiMassimiliano CoccaChristian FuchsbergerMathias GorskiAnselm HoppmannKatrin HornMan LiJonathan MartenDamia NoceTeresa NutileSanaz SedaghatGardar SveinbjornssonBamidele O TayoPeter J van der MostYizhe XuZhi YuLea GerstnerJohan ÄrnlövStephan J L BakkerDaniela BaptistaMary L BiggsEric BoerwinkleHermann BrennerRalph BurkhardtRobert J CarrollMiao-Li CheeMiao-Ling CheeMengmeng ChenChing-Yu ChengJames P CookJosef CoreshTanguy CorreJohn DaneshMartin H de BorstAlessandro De GrandiRenée de MutsertAiko P J de VriesFrauke DegenhardtKatalin DittrichJasmin DiversKai-Uwe EckardtGeorg B EhretKarlhans EndlichJanine F FelixOscar H FrancoAndre FrankeBarry I FreedmanSandra Freitag-WolfRon T GansevoortVilmantas GiedraitisMartin GögeleFranziska Grundner-CulemannDaniel F GudbjartssonVilmundur G GudnasonPavel HametTamara B HarrisAndrew A HicksHilma HolmValencia Hui Xian FooShih-Jen HwangMohammad Arfan IkramErik IngelssonVincent W V JaddoeJohanna JakobsdottirNavya Shilpa JosyulaBettina JungMika KähönenChiea Chuen KhorWieland KiessWolfgang KoenigAntje KörnerPeter KovacsHolly KramerBernhard K KrämerFlorian KronenbergLeslie A LangeCarl D LangefeldJeannette Jen-Mai LeeTerho LehtimäkiWolfgang LiebSu-Chi LimLars LindCecilia M LindgrenJian-Jun LiuMarkus LoefflerLeo-Pekka LyytikainenAnubha MahajanJoseph C MaranvilleDeborah MascalzoniBarbara McMullenChrista MeisingerThomas MeitingerKozeta MilikuDennis O Mook-KanamoriMartina Müller-NuraysidJosyf C MychaleckyiMatthias NauckKjell NikusBoting NingRaymond NoordamJeffrey O' ConnellIsleifur OlafssonNicholette D D AllredAnnette PetersAnna I PodgornaiaBelen PonteTanja PoulainPeter P PramstallerTon J RabelinkLaura M RaffieldDermot F ReillyRainer RettigMyriam RheinbergerKenneth M RiceFernando RivadeneiraHeiko RunzKathleen A RyanSabanayagam CharumathiKai-Uwe SaumBen SchöttkerChristian M ShafferYuan ShiAlbert Vernon SmithKonstantin StrauchMichael StumvollBenjamin B SunSilke SzymczakE-Shyong TaiNicholas Y Q TanKent D TaylorAndrej TerenYih-Chung ThamJoachim ThieryChris H L ThioHauke ThomsenUnnur ThorsteinsdottirAnke TönjesJohanne TremblayAndre G UitterlindenPim van der HarstNiek VerweijSuzanne VogelezangLinus VölkerMelanie WaldenbergerChaolong WangOtis D WilsonCharlene WongTien-Yin WongQiong YangMasayuki YasudaShreeram AkileshMurielle BochudCarsten A BögerOlivier DevuystTodd L EdwardsKevin HoAndrew P MorrisAfshin ParsaSarah A PendergrassBruce M PsatyJerome I RotterKári StefánssonJames G WilsonKatalin SusztákHarold SniederIris M HeidMarkus ScholzAdam S ButterworthAdriana M HungCristian PattaroAnna Kottgen
Published in: Nature communications (2019)
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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