Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

被引：31

作者：

Bostrom, Meredith A. ^{[1
]}

Kao, W. H. Linda ^{[2
]}

Li, Man ^{[2
]}

Abboud, Hanna E. ^{[3
]}

Adler, Sharon G. ^{[4
]}

Iyengar, Sudha K. ^{[5
]}

Kimmel, Paul L. ^{[6
]}

Hanson, Robert L. ^{[7
]}

Nicholas, Susanne B. ^{[8
]}

Rasooly, Rebekah S. ^{[6
]}

Sedor, John R. ^{[5
]}

Coresh, Josef ^{[2
]}

Kohn, Orly F. ^{[9
]}

Leehey, David J. ^{[10
]}

Thornley-Brown, Denyse ^{[11
]}

Bottinger, Erwin P. ^{[12
]}

Lipkowitz, Michael S. ^{[13
]}

Meoni, Lucy A. ^{[2
]}

Klag, Michael J. ^{[2
]}

Lu, Lingyi ^{[1
]}

Hicks, Pamela J. ^{[1
]}

Langefeld, Carl D. ^{[1
]}

Parekh, Rulan S. ^{[2
,14
]}

Bowden, Donald W. ^{[1
]}

Freedman, Barry I. ^{[1
]}

机构：

[1] Wake Forest Sch Med, Nephrol Sect, Winston Salem, NC 27157 USA

[2] Johns Hopkins Univ, Baltimore, MD USA

[3] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA

[4] Harbor UCLA Med Ctr, Los Angeles, CA USA

[5] Case Western Reserve Univ, Sch Med, Cleveland, OH USA

[6] NIDDK, NIH, Bethesda, MD USA

[7] NIDDK, NIH, Phoenix, AZ USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[9] Univ Chicago, Chicago, IL 60637 USA

[10] Loyola Univ, Chicago, IL 60611 USA

[11] Univ Alabama, Birmingham, AL USA

[12] Mt Sinai Sch Med, New York, NY USA

[13] Georgetown Univ, Sch Med, Washington, DC USA

[14] Univ Toronto, Toronto, ON, Canada

来源：

AMERICAN JOURNAL OF KIDNEY DISEASES | 2012年 / 59卷 / 02期

基金：

美国医疗保健研究与质量局; 美国国家卫生研究院;

关键词：

African American; APOL1; CFH; end-stage renal disease; Family Investigation of Nephropathy and Diabetes (FIND); focal segmental glomerulosclerosis (FSGS); hypertension; STAGE RENAL-DISEASE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GENOME-WIDE ASSOCIATION; HEMOLYTIC-UREMIC SYNDROME; NEPHROTIC SYNDROME; SUSCEPTIBILITY LOCI; GLOMERULAR PROTEIN; KIDNEY-DISEASE; POLYMORPHISMS; MUTATIONS;

D O I：

10.1053/j.ajkd.2011.09.020

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Background: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans. Study Design: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. Setting & Participants: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls. Predictors: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes. Outcomes: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1. Results: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 x 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 x 10(-7)) with replication in FIND (P = 5.0 x 10(-21) and 1.9 x 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 x 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001). Limitations: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy. Conclusions: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes. Am J Kidney Dis. 59(2): 210-221. (C) 2012 by the National Kidney Foundation, Inc.

引用

页码：210 / 221

页数：12

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