Bonomo Jason A, Ng Maggie C Y, Palmer Nicholette D, Keaton Jacob M, Larsen Chris P, Hicks Pamela J, Langefeld Carl D, Freedman Barry I, Bowden Donald W
Departments of Molecular Medicine and Translational Science, Center for Human Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina; and.
Center for Human Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina; and Biochemistry.
Clin J Am Soc Nephrol. 2014 Aug 7;9(8):1434-40. doi: 10.2215/CJN.00290114. Epub 2014 Jun 19.
Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed.
Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests.
Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.
非裔美国人患糖尿病性和非糖尿病性终末期肾病的假定遗传风险很高。
设计、地点、参与者与测量：对T2D-GENES研究中患有2型糖尿病终末期肾病的非裔美国人以及非糖尿病、无肾病的对照者的外显子组测序数据进行了评估（发现阶段，529例患者和535例对照），重点关注NPHS1中的错义变异。然后在独立的2型糖尿病终末期肾病样本（复制阶段，1305例患者和760例对照）、非糖尿病终末期肾病样本（1705例）以及仅患有2型糖尿病、无肾病的样本（503例）中对相关变异进行评估。所有参与者均于1991年至今从美国东南部的透析机构和内科诊所招募。从外显子组测序资源中鉴定出其他NPHS1错义变异，进行基因分型，然后进行序列核关联测试。
初始分析确定rs35238405（T233A；次要等位基因频率 = 0.0096）与2型糖尿病终末期肾病相关（校正混合比例后P = 0.042；校正混合比例 + APOL1后P = 0.080；比值比分别为2.89和2.36）；在独立的2型糖尿病终末期肾病样本（P = 0.018；比值比，4.30）和非糖尿病终末期肾病样本（P = 0.016；比值比，4.48）中得到验证。在一项综合分析（所有终末期肾病患者与所有对照）中，T233A与全因性终末期肾病相关（P = 0.0038；比值比，2.82；3270例患者和1187例对照）。在序列核关联测试中校正混合比例和APOL1后，P值 < 0.001。在全基因座单变异关联测试中，另外两个变异（H800R和Y1174H）名义上与预防终末期肾病相关（P = 0.036；比值比，0.44；P = 0.0084；比值比，0.040）。
NPHS1中的编码变异与非裔美国人常见肾病形式的风险和预防均相关。
