Faculty Bibliography

Complement cascade plasma proteins play a complex role in the etiopathogenesis of systemic lupus erythematosus (SLE). Hereditary C1q deficiency has been strongly related to SLE; however, there are very few published SLE studies that evaluate the polymorphisms of genes encoding for C1q (A, B and C). In this study, we evaluated 17 single nucleotide polymorphisms (SNPs) across 37 kb of C1QA, C1QB and C1QC in a lupus cohort of individuals of the African-American and Hispanic origin. In a case-only analysis, a significant association at multiple SNPs in the C1QA gene was detected in African Americans with kidney nephritis (best P=4.91 x 10(-6)). In addition, C1QA was associated with SLE in African Americans with a lack of nephritis and accompanying photosensitivity when compared with that in normal controls (P=6.80 x 10(-6)). A similar trend was observed in the Hispanic subjects (P=0.003). Quantitative analysis showed that some SNPs in C1q genes might be correlated with C3 complement levels in an additive model among African Americans (best P=0.0001). The C1QA gene is associated with subphenotypes of lupus in the African-American and Hispanic subjects. Further studies with higher SNP densities in this region and other complement components are necessary to elucidate the complex genetics and phenotypic interactions between complement components and SLE.

Recent evidence suggests that mitochondrial uncoupling protein 2 (UCP2) in pancreatic beta-cells plays a crucial role in insulin production and secretion. We hypothesized that 2 UCP2 polymorphisms, a -55C/T (Ala55Val) substitution in exon 4 and an exon 8 insertion, would alter the acute insulin response to glucose (AIRg). Subjects were 155 African American (AA) and European American (EA) women. Body composition was determined by dual-energy x-ray absorptiometry. Insulin sensitivity and AIRg were measured with an intravenous glucose tolerance test and minimal modeling. To account for the confounding effects of population stratification, estimates of African admixture were obtained from approximately 35 ancestry-informative markers. Uncoupling protein 2 genotyping was conducted with gel electrophoresis. Information was analyzed using mixed linear models. A positive association between the -55C/T homozygous mutation and AIRg was identified in the total sample (P < .01) and independently in EA women (P = .02) but not AA women. The exon 8 insertion did not significantly affect AIRg. No interaction effects of the 2 polymorphisms on AIRg were noted. These results indicate that AIRg is associated with the -55C/T UCP2 homozygous mutation and that the presence of this mutation could alter postchallenge insulin concentration.

African Americans have high incidence rates of end-stage renal disease (ESRD) labeled as due to hypertension. As recent studies showed strong association with idiopathic and HIV-related focal segmental glomerulosclerosis and non-muscle myosin heavy chain 9 (MYH9) gene polymorphisms in this ethnic group, we tested for MYH9 associations in a variety of kidney diseases. Fifteen MYH9 single-nucleotide polymorphisms were evaluated in 175 African Americans with chronic glomerulonephritis-associated ESRD, 696 African Americans reportedly with hypertension-associated ESRD, and 948 control subjects without kidney disease. Significant associations were detected with 14 of the 15 polymorphisms in all 871 non-diabetic patients with ESRD. In hypertension-associated ESRD cases alone, significant associations were found with 13 MYH9 polymorphisms and the previously reported E1 haplotype. Thus, hypertension-associated ESRD in African Americans is substantially related to MYH9 gene polymorphisms and this may explain the poor response to blood pressure control in those diagnosed with hypertensive nephrosclerosis. It is possible that many African Americans classified as having hypertension-associated ESRD have occult MYH9-associated segmental or global glomerulosclerosis. Our study shows that gene-environment and/or gene-gene interactions may initiate kidney disease in genetically susceptible individuals, because African Americans homozygous for MYH9 risk alleles do not universally develop kidney disease.

With the advent of powerful computers, simulation studies are becoming an important tool in statistical methodology research. However, computer simulations of a specific process are only as good as our understanding of the underlying mechanisms. An attractive supplement to simulations is the use of plasmode datasets. Plasmodes are data sets that are generated by natural biologic processes, under experimental conditions that allow some aspect of the truth to be known. The benefit of the plasmode approach is that the data are generated through completely natural processes, thus circumventing the common concern of the realism and accuracy of computer simulated data. The estimation of admixture, or the proportion of an individual's genome that originates from different founding populations, is a particularly difficult research endeavor that is well suited to the use of plasmodes. Current methods have been tested with simulations of complex populations where the underlying mechanisms such as the rate and distribution of recombination are not well understood. To demonstrate the utility of this method data derived from mouse crosses is used to evaluate the effectiveness of several admixture estimation methodologies. Each cross shares a common founding population so that the ancestry proportion for each individual is known, allowing for the comparison of true and estimated individual admixture values. Analysis shows that the different estimation methodologies (Structure, AdmixMap and FRAPPE) examined all perform well with simple datasets. However, the performance of the estimation methodologies varied greatly when applied to a plasmode consisting of three founding populations. The results of these examples illustrate the utility of plasmodes in the evaluation of statistical genetics methodologies.

OBJECTIVE:The Gullah-speaking African American population from the Sea Islands of South Carolina is characterized by a low degree of European admixture and high rates of type 2 diabetes and diabetic complications. Affected relative pairs with type 2 diabetes were recruited through the Sea Islands Genetic African American Registry (Project SuGAR). RESEARCH DESIGN AND METHODS/METHODS:We conducted a genome-wide linkage scan, genotyping 5,974 single nucleotide polymorphisms in 471 affected subjects and 50 unaffected relatives from 197 pedigrees. Data were analyzed using a multipoint engine for rapid likelihood inference and ordered subsets analyses (OSAs) for age at type 2 diabetes diagnosis, waist circumference, waist-to-hip ratio, and BMI. We searched for heterogeneity and interactions using a conditional logistic regression likelihood approach. RESULTS:Linkage peaks on chromosome 14 at 123-124 cM were detected for type 2 diabetes (logarithm of odds [LOD] 2.10) and for the subset with later age at type 2 diabetes diagnosis (maximum LOD 4.05). Two linkage peaks on chromosome 7 were detected at 44-45 cM for type 2 diabetes (LOD 1.18) and at 78 cM for type 2 diabetes (LOD 1.64) and the subset with earlier age at type 2 diabetes diagnosis (maximum LOD 3.93). The chromosome 14 locus and a peak on 7p at 29.5 cM were identified as important in the multilocus model. Other regions that provided modest evidence for linkage included chromosome 1 at 167.5 cM (LOD 1.51) and chromosome 3 at 121.0 cM (LOD 1.61). CONCLUSIONS:This study revealed a novel type 2 diabetes locus in an African American population on 14q that appears to reduce age of disease onset and confirmed two loci on chromosome 7.

OBJECTIVES/OBJECTIVE:Structured association tests (SAT), like any statistical model, assumes that all variables are measured without error. Measurement error can bias parameter estimates and confound residual variance in linear models. It has been shown that admixture estimates can be contaminated with measurement error causing SAT models to suffer from the same afflictions. Multiple imputation (MI) is presented as a viable tool for correcting measurement error problems in SAT linear models with emphasis on correcting measurement error contaminated admixture estimates. METHODS:Several MI methods are presented and compared, via simulation, in terms of controlling Type I error rates for both non-additive and additive genotype coding. RESULTS:Results indicate that MI using the Rubin or Cole method can be used to correct for measurement error in admixture estimates in SAT linear models. CONCLUSION/CONCLUSIONS:Although MI can be used to correct for admixture measurement error in SAT linear models, the data should be of reasonable quality, in terms of marker informativeness, because the method uses the existing data to borrow information in which to make the measurement error corrections. If the data are of poor quality there is little information to borrow to make measurement error corrections.

BACKGROUND:MYH9 is a podocyte-expressed gene encoding nonmuscle myosin IIA that is associated with idiopathic and human immunodeficiency virus-associated focal segmental glomerulosclerosis (FSGS) and hypertensive end-stage renal disease in African Americans. METHODS:Four single nucleotide polymorphisms comprising the major MYH9 E1 risk haplotype were tested for association with estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in 2,903 HyperGEN participants (1,458 African Americans (AA) in 895 families and 1,445 European Americans (EA) in 859 families) to determine the role of MYH9 in subclinical nephropathy. Association analyses employed general linear models in unrelated probands and generalized estimating equations in families. Adjustment was performed for age, sex, diabetes, BMI, medications, and mean arterial pressure separately in each race. RESULTS:Mean (SD) eGFR and ACR were 74.3 (16.0) ml/min/1.73 m(2) and 20.3 (119.9) mg/g in EA, and 88.6 (20.9) ml/min/1.73 m(2) and 76.8 (394.5) mg/g in AA (both p < 0.0001 across ethnicities). Urine ACR was associated with rs3752462 (p = 0.01) and rs4821481 (p = 0.05) in unrelated AA and with rs4821481 (p = 0.03), rs2032487 (p = 0.04) and the E1 3224 haplotype (p = 0.013) in AA families. Single nucleotide polymorphisms and the haplotype were not associated with ACR in EA or with eGFR in either ethnic group. CONCLUSIONS:MYH9 variants are associated with albuminuria in hypertensive AA. The strength of the association was weaker than that in FSGS and hypertensive end-stage renal disease. MYH9 risk variants appear to be associated with primary FSGS with secondary hypertension, although nephrosclerosis may develop in response to hypertension in subjects homozygous for the MYH9 E1 risk haplotype.

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.

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 (r2 = 0.101; P = 0.019) and in the combined set (r2 = 0.131; P = 3.57 x 10(-5)). The absolute difference between frequencies in parental populations, absolute delta, 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.

OBJECTIVE:Several whole-genome association studies have reported identification of type 2 diabetes susceptibility genes in various European-derived study populations. Little investigation of these loci has been reported in other ethnic groups, specifically African Americans. Striking differences exist between these populations, suggesting they may not share identical genetic risk factors. Our objective was to examine the influence of type 2 diabetes genes identified in whole-genome association studies in a large African American case-control population. RESEARCH DESIGN AND METHODS/METHODS:Single nucleotide polymorphisms (SNPs) in 12 loci (e.g., TCF7L2, IDE/KIF11/HHEX, SLC30A8, CDKAL1, PKN2, IGF2BP2, FLJ39370, and EXT2/ALX4) associated with type 2 diabetes in European-derived populations were genotyped in 993 African American type 2 diabetic and 1,054 African American control subjects. Additionally, 68 ancestry-informative markers were genotyped to account for the impact of admixture on association results. RESULTS:Little evidence of association was observed between SNPs, with the exception of those in TCF7L2, and type 2 diabetes in African Americans. One TCF7L2 SNP (rs7903146) showed compelling evidence of association with type 2 diabetes (admixture-adjusted additive P [P(a)] = 1.59 x 10(-6)). Only the intragenic SNP on 11p12 (rs9300039, dominant P [P(d)] = 0.029) was also associated with type 2 diabetes after admixture adjustments. Interestingly, four of the SNPs are monomorphic in the Yoruba population of the HAPMAP project, with only the risk allele from the populations of European descent present. CONCLUSIONS:Results suggest that these variants do not significantly contribute to interindividual susceptibility to type 2 diabetes in African Americans. Consequently, genes contributing to type 2 diabetes in African Americans may, in part, be different from those in European-derived study populations. High frequency of risk alleles in several of these genes may, however, contribute to the increased prevalence of type 2 diabetes in African Americans.