Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.
Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.
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Teumer A;Tin A;Sorice R;Gorski M;Yeo NC;Chu AY;Li M;Li Y;Mijatovic V;Ko YA;Taliun D;Luciani A;Chen MH;Yang Q;Foster MC;Olden M;Hiraki LT;Tayo BO;Fuchsberger C;Dieffenbach AK;Shuldiner AR;Smith AV;Zappa AM;Lupo A;Kollerits B;Ponte B;Stengel B;Krämer BK;Paulweber B;Mitchell BD;Hayward C;Helmer C;Meisinger C;Gieger C;Shaffer CM;Müller C;Langenberg C;Ackermann D;Siscovick D;DCCT/EDIC;Boerwinkle E;Kronenberg F;Ehret GB;Homuth G;Waeber G;Navis G;Gambaro G;Malerba G;Eiriksdottir G;Li G;Wichmann HE;Grallert H;Wallaschofski H;Völzke H;Brenner H;Kramer H;Mateo Leach I;Rudan I;Hillege HL;Beckmann JS;Lambert JC;Luan J;Zhao JH;Chalmers J;Coresh J;Denny JC;Butterbach K;Launer LJ;Ferrucci L;Kedenko L;Haun M;Metzger M;Woodward M;Hoffman MJ;Nauck M;Waldenberger M;Pruijm M;Bochud M;Rheinberger M;Verweij N;Wareham NJ;Endlich N;Soranzo N;Polasek O;van der Harst P;Pramstaller PP;Vollenweider P;Wild PS;Gansevoort RT;Rettig R;Biffar R;Carroll RJ;Katz R;Loos RJ;Hwang SJ;Coassin S;Bergmann S;Rosas SE;Stracke S;Harris TB;Corre T;Zeller T;Illig T;Aspelund T;Tanaka T;Lendeckel U;Völker U;Gudnason V;Chouraki V;Koenig W;Kutalik Z;O'Connell JR;Parsa A;Heid IM;Paterson AD;de Boer IH;Devuyst O;Lazar J;Endlich K;Susztak K;Tremblay J;Hamet P;Jacob HJ;Böger CA;Fox CS;Pattaro C;Köttgen A
尿中白蛋白浓度升高（白蛋白尿）是糖尿病肾病的标志，与终末期肾病和心血管事件的风险增加相关。为了深入了解蛋白尿的病理生理机制，我们对多达5，825名欧洲血统的糖尿病患者和多达46，061名非糖尿病患者进行了全基因组关联研究和独立复制的荟萃分析，随后进行了功能研究。已知的CUBN（编码cubilin）变异与尿白蛋白-肌酐比值（UACR）的相关性在总体样本中得到证实（P = 2.4 × 10−10）。检测到基因与糖尿病的相互作用，并确认了HS 6ST 1和近RAB 38/CTSC的变异。这些基因座的单核苷酸多态性证明了对患有糖尿病但并非没有糖尿病的个体的UACR的遗传效应。每个次要等位基因的平均UACR变化在HS 6ST 1中为21%（P = 6.3 × 10-7），在RAB 38/CTSC中为13%（P = 5.8 × 10 - 7）。使用链脲佐菌素诱导的糖尿病Rab 38基因敲除大鼠和对照大鼠的实验显示，Rab 38基因敲除大鼠的尿白蛋白浓度较高，近端小管细胞表面的megalin和cubilin含量较对照大鼠减少。与对照组相比，糖尿病肾病患者肾小管中RAB 38的相对表达更高。这里确定的基因座证实了已知的途径，并强调了影响白蛋白尿的新途径。
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.