A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.
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作者：
Casanova F;Wood AR;Yaghootkar H;Beaumont RN;Jones SE;Gooding KM;Aizawa K;Strain WD;Hattersley AT;Khan F;Shore AC;Frayling TM;Tyrrell J
白蛋白-肌酐比值（ACR）升高是微血管损伤和肾脏疾病的一个指标。我们旨在确定与ACR升高相关的遗传变异，并研究携带多个ACR升高等位基因与代谢和血管相关疾病的关系。我们在发现阶段对来自英国生物银行的437,027名个体进行了ACR全基因组关联研究，比之前的研究多了54,527人，并在独立研究中跟踪了我们的发现。我们在56个基因座中发现了62个与ACR的独立关联（P<5 × 10-8），其中20个以前没有报道过。通路分析和鉴定出62个变异中的20个（r值为2 - 0 - 0.8）与至少16个相关代谢和血管性状的信号一致，表明有多种途径导致ACR水平升高。排除CUBN位点的变异（已知通过影响肾脏吸收改变ACR）后，ACR遗传风险评分与高血压的高风险相关，与2型糖尿病和中风的相关性较弱。对于CUBN位点的一些罕见基因型组合，大多数个体的ACR水平高于微量白蛋白尿临床阈值。与我们的假设相反，携带更多CUBN acr升高等位基因且高于临床阈值的个体患血管疾病的频率更高。CUBN等位基因对ACR的影响在糖尿病患者中是前者的两倍，这一结果适用于模拟相互作用的优化算法方法，验证了先前报道的基因-糖尿病相互作用（P≤4x10-5）。综上所述，多种遗传机制和性状导致了ACR的变异。
Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular related disease. We performed a genome-wide association study of ACR using 437,027 individuals from the UK Biobank in the discovery phase, 54,527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P<5x10-8), of which 20 were not previously reported. Pathway analyses and the identification of 20 of the 62 variants (at r 2>0.8) coinciding with signals for at least sixteen related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes – a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P≤4x10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
腰围比与心脏代谢性状，2型糖尿病和冠状动脉疾病的遗传关联。
DOI：
10.1001/jama.2016.21042
发表时间：
2017-02-14
期刊：
JAMA
影响因子：
--
作者：
Emdin CA;Khera AV;Natarajan P;Klarin D;Zekavat SM;Hsiao AJ;Kathiresan S
通讯作者：
Kathiresan S
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
30.8
作者：
Loh, Po-Ru;Tucker, George;Bulik-Sullivan, Brendan K.;Vilhjalmsson, Bjarni J.;Finucane, Hilary K.;Salem, Rany M.;Chasman, Daniel I.;Ridker, Paul M.;Neale, Benjamin M.;Berger, Bonnie;Patterson, Nick;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
13.2
作者：
Pinto-Sietsma, SJ;Navis, G;de Jong, PE
通讯作者：
de Jong, PE