全基因组关联研究确定了非裔美国人中2型糖尿病所致终末期肾病的新基因座。
Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans.
作者信息
Guan Meijian, Keaton Jacob M, Dimitrov Latchezar, Hicks Pamela J, Xu Jianzhao, Palmer Nicholette D, Ma Lijun, Das Swapan K, Chen Yii-Der I, Coresh Josef, Fornage Myriam, Franceschini Nora, Kramer Holly, Langefeld Carl D, Mychaleckyj Josyf C, Parekh Rulan S, Post Wendy S, Rasmussen-Torvik Laura J, Rich Stephen S, Rotter Jerome I, Sedor John R, Thornley-Brown Denyse, Tin Adrienne, Wilson James G, Freedman Barry I, Bowden Donald W, Ng Maggie C Y
机构信息
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
出版信息
Hum Genomics. 2019 May 15;13(1):21. doi: 10.1186/s40246-019-0205-7.
BACKGROUND
End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants.
RESULTS
Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis.
CONCLUSIONS
Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.
背景
终末期肾病（ESKD）是一个重大的公共卫生问题，对非裔美国人（AA）的影响尤为严重。2型糖尿病（T2D）是美国ESKD的主要病因，而揭示糖尿病肾病（DKD）遗传易感性的努力取得的成功有限。一项先前针对患有T2D-ESKD的非裔美国人的全基因组关联研究（GWAS）通过增加更多非裔美国人病例和对照，并将基因型推算至更高密度的1000基因组参考面板进行了扩展。发现分析包括3432例T2D-ESKD病例和6977例非糖尿病非肾病对照（N = 10409），随后在2756例T2D非肾病对照中进行判别分析，以排除与T2D相关的变异。
结果
位于RND3/RBM43、SLITRK3、ENPP7、GNG7和APOL1内或附近的六个独立变异与T2D-ESKD达到全基因组显著关联（P < 5×10）。在对1910例非糖尿病ESKD病例和908例非糖尿病非肾病对照进行扩展分析后，对5342例非裔美国人全因ESKD病例和6977例非裔美国人非糖尿病非肾病对照的荟萃分析揭示了EFNB2处另一个新的全因ESKD位点（rs77113398；P = 9.84×10；OR = 1.94）。排除APOL1肾风险基因型携带者后，在GRAMD3和MGAT4C处发现另外两个全基因组显著的T2D-ESKD相关位点。GNG7处的另一个变异（rs373971520；P = 2.17×10，OR = 1.46）在APOL1阴性分析中仍与全因ESKD相关。
结论
研究结果为T2D非裔美国人中与晚期肾病相关的遗传因素提供了进一步证据。
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