Guan Meijian, Keaton Jacob M, Dimitrov Latchezar, Hicks Pamela J, Xu Jianzhao, Palmer Nicholette D, Wilson James G, Freedman Barry I, Bowden Donald W, Ng Maggie C Y
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Kidney Int Rep. 2018 Mar 14;3(4):867-878. doi: 10.1016/j.ekir.2018.03.002. eCollection 2018 Jul.
Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs.
Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations ( < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals.
A total of 11 suggestive T2D-ESKD associations ( < 1 x 10) from 8 loci () were apparent in the meta-analysis. Exclusion of renal-risk genotype carriers identified 3 additional suggestive loci (). Rs41302867 in displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; = 1.2 x 10 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals).
Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs.
与欧裔美国人相比，非裔美国人（AA）患终末期肾病（ESKD）的风险更高。全基因组关联研究（GWAS）已在患有和未患有糖尿病的患者中鉴定出70多个与肾功能和慢性肾病（CKD）相关的基因变异。然而，这些变异仅解释了疾病易感性的一小部分。本研究探讨了编码基因变异对AA中2型糖尿病（T2D）所致ESKD和晚期CKD风险的影响。
在发现阶段，对456例AA T2D-ESKD病例和936例AA非糖尿病、无肾病对照个体进行外显子组测序。采用混合逻辑回归模型进行关联分析。在另外2020例T2D-ESKD病例和1121例非糖尿病、无肾病对照个体中重复名义关联（<0.05）。对4533个发现和重复样本进行荟萃分析。在另外1910例非糖尿病ESKD和219例T2D-ESKD病例以及912例AA非糖尿病无肾病对照个体中测试推定的T2D-ESKD关联。
荟萃分析中共有来自8个基因座（）的11个提示性T2D-ESKD关联（<1×10）明显。排除肾风险基因型携带者后，又发现了3个提示性基因座（）。中Rs41302867与T2D-ESKD和非糖尿病ESKD显示出一致的关联（优势比：0.47；在4605例全因ESKD和2969例非糖尿病无肾病对照个体中=1.2×10）。
我们的研究结果表明，编码基因变异与AA中T2D-ESKD的易感性有关。
