Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans

被引：30

作者：

Guan, Meijian ^{[1
]}

Ma, Jun ^{[2
,3
]}

Keaton, Jacob M. ^{[1
,4
]}

Dimitrov, Latchezar ^{[1
]}

Mudgal, Poorva ^{[1
]}

Stromberg, Mary ^{[1
]}

Bonomo, Jason A. ^{[1
,4
]}

Hicks, Pamela J. ^{[1
]}

Freedman, Barry I. ^{[2
,4
]}

Bowden, Donald W. ^{[1
,4
,5
]}

Ng, Maggie C. Y. ^{[1
,4
]}

机构：

[1] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Med Ctr Blvd, Winston Salem, NC 27157 USA

[2] Wake Forest Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC USA

[3] Shanghai Jiao Tong Univ, Sch Med, Dept Nephrol, Ruijin Hosp, Shanghai, Peoples R China

[4] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC 27157 USA

[5] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA

来源：

HUMAN GENETICS | 2016年 / 135卷 / 11期

基金：

中国国家自然科学基金;

关键词：

FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GENOME-WIDE ASSOCIATION; RENAL-FAILURE; NEPHROPATHY; SUSCEPTIBILITY; MUTATIONS; NEPHRIN; CD2AP; PATHOGENICITY; MECHANISMS;

D O I：

10.1007/s00439-016-1714-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P (corr) < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P (corr) < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.

引用

页码：1251 / 1262

页数：12

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