Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM–ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r 2 = 0.101; P = 0.019) and in the combined set (r 2 = 0.131; P = 3.57 × 10−5). The absolute difference between frequencies in parental populations, absolute , was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture.
"All protocols were approved by the Wake Forest University Institutional Review Board. Percentage of African ancestry was calculated for each individual from genotyping 70 ancestry informative markers (AIMs), as previously published (Keene et al. 2008 "
[Show abstract][Hide abstract] ABSTRACT: African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA pools were genotyped in duplicate on the Illumina HumanHap550-Duo BeadChip. Normalization methods were developed and applied to array intensity values to reduce inter-array variance. Allele frequencies were calculated from normalized channel intensities and compared between case and control pools. Three SNPs had p values of <1.0E-6: rs4462445 (ch 13), rs4821469 (ch 22) and rs8077346 (ch 17). After normalization, top scoring SNPs (n = 65) were genotyped individually in 464 of the original cases and 478 of the controls, with replication in 336 non-DM ESRD cases and 363 non-nephropathy controls. Sixteen SNPs were associated with non-DM ESRD (p < 7.7E-4, Bonferroni corrected). Twelve of these SNPs are in or near the MYH9 gene. The four non-MYH9 SNPs that were associated with non-DM ESRD in the pooled samples were not associated in the replication set. Five SNPs that were modestly associated in the pooled samples were more strongly associated in the replication and/or combined samples. This is the first GWAS for non-DM ESRD in African Americans using pooled DNA. We demonstrate strong association between non-DM ESRD in African Americans with MYH9, and have identified additional candidate loci.
Human Genetics 08/2010; 128(2):195-204. DOI:10.1007/s00439-010-0842-3 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in the adiponectin gene (ADIPOQ) have been associated with type 2 diabetes and diabetic nephropathy in type 1 diabetes, in mostly European-derived populations.
A comprehensive association analysis of 24 single-nucleotide polymorphisms (SNPs) in the adiponectin gene was performed for type 2 diabetes and diabetic nephropathy in African Americans.
The minor allele (A) in a single SNP in intron 1 (rs182052) was associated with diabetic nephropathy (P = 0.0015, odds ratio [OR] 1.37, CI 1.13-1.67, dominant model) in an African American sample of 851 case subjects with diabetic nephropathy and 871 nondiabetic control subjects in analyses incorporating adjustment for varying levels of racial admixture. This association remained significant after adjustment of the data for BMI, age, and sex (P = 0.0013-0.0004). We further tested this SNP for association with longstanding type 2 diabetes without nephropathy (n = 317), and evidence of association was also significant (P = 0.0054, OR 1.46, CI 1.12-1.91, dominant model) when compared with the same set of 871 nondiabetic control subjects. Combining the type 2 diabetes and diabetic nephropathy samples into a single group of case subjects (n = 1,168) resulted in the most significant evidence of association (P = 0.0003, OR 1.40, CI 1.17-1.67, dominant model). Association tests between age at onset of type 2 diabetes and the rs182052 genotypes also revealed significant association between the presence of the minor allele (A/A or A/G) and earlier onset of type 2 diabetes.
The SNP rs182052 in intron 1 of the adiponectin gene is associated with type 2 diabetes in African Americans.
[Show abstract][Hide abstract] ABSTRACT: Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 (MYH9), and apolipoprotein L1 (APOL1) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.
Kidney International 08/2011; 80(12):1339-43. DOI:10.1038/ki.2011.286 · 8.56 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.