A genome-wide association study for diabetic nephropathy genes in African Americans.

A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD.

Genome-wide association of BMI in African Americans.

Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with obesity in Europeans but results in other ethnicities are less convincing. Here, we report a two-stage GWAS of BMI in African Americans. The GWAS was performed using the Affymetrix 6.0 platform in 816 nondiabetic and 899 diabetic nephropathy subjects. 746,626 single-nucleotide polymorphisms (SNPs) were tested for association with BMI after adjustment for age, gender, disease status, and population structure. Sixty high scoring SNPs that showed nominal association in both GWAS cohorts were further replicated in 3,274 additional subjects in four replication cohorts and a meta-analysis was computed. Meta-analysis of 4,989 subjects revealed five SNPs (rs6794092, rs268972, rs2033195, rs815611, and rs6088887) at four loci showing consistent associations in both GWAS (P < 0.0001) and replication cohorts (P < 0.05) with combined P values range from 2.4 × 10(-6) to 5 × 10(-5). These loci are located near PP13439-TMEM212, CDH12, MFAP3-GALNT10, and FER1L4 and had effect sizes between 0.091 and 0.167 s.d. unit (or 0.67-1.24 kg/m(2)) of BMI for each copy of the effect allele. Our findings suggest the presence of novel loci potentially associated with adiposity in African Americans. Further replication and meta-analysis in African Americans and other populations will shed light on the role of these loci in different ethnic populations.

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

Linkage heterogeneity of end-stage renal disease on human chromosome 10.

BACKGROUND: The human syntenic region of the rodent renal failure-1 gene (Rf1), an attractive candidate region for end-stage renal disease (ESRD) susceptibility, is located on chromosome 10q24-q26. In an attempt to assess for linkage between markers on human chromosome 10 and ESRD, we performed a linkage analysis in 356 African American sib pairs concordant for ESRD [199 sib pairs concordant for non-diabetic etiologies (hypertension-associated, chronic glomerulonephritis and unknown) and 157 sib pairs concordant for diabetic ESRD]. METHODS: Linkage was tested between 30 polymorphic markers spanning chromosome 10 and ESRD using GeneHunter software. RESULTS: In all 356 sib pairs, the maximum likelihood ratio z-score (Zlr) occurred near locus D10S677 (Zlr = 3.33, P = 0.0004, lod = 3.40), with a lesser peak near D10S1435 (Zlr = 1.77, P = 0.04, lod = 1.42). The locus at D10S677 contributed significantly to both diabetic ESRD (Zlr = 2.39, P = 0.008, lod = 2.08) and non-diabetic ESRD (Zlr = 2.35, P = 0.009, lod = 2.03). Additionally, the D10S677 peak was observed in both early onset (< or =50 years) and late onset (>50 years) ESRD (Zlr = 2.96, P = 0.002, lod = 2.82 in early onset and Zlr = 1.96, P = 0.03, lod = 1.60 in late onset ESRD families, respectively). The lesser peak at D10S1435 was observed in families with non-diabetic etiologies of ESRD (Zlr = 1.94, P = 0.02, lod = 1.58) and in those with early onset ESRD (Zlr = 1.89, P = 0.03, lod = 1.53). CONCLUSIONS: These results suggest that the region near D10S677, adjacent to the human homolog of the Rf1 gene, contributes to ESRD susceptibility in African Americans. They confirm that the region on 10p, near D10S1435, appears to be involved in early onset, non-diabetic etiologies of ESRD in African Americans.