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1.  The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture 
Arthritis and rheumatism  2008;58(2):349-358.
Objective
To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population.
Methods
In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti-CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.
Results
The frequency of SE-containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody–negative RA (P = 0.01, by chi-square test).
Conclusion
HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ~50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.
doi:10.1002/art.23166
PMCID: PMC3726059  PMID: 18240241
2.  Association of Single Nucleotide Polymorphisms (SNPs) in CCR6, TAGAP and TNFAIP3 with Rheumatoid Arthritis in African Americans 
Arthritis and Rheumatism  2012;64(5):1355-1358.
Objective
We previously reported an analysis of single nucleotide polymorphisms (SNPs) in three validated European rheumatoid arthritis (RA) susceptibility loci, TAGAP, TNFAIP3, and CCR6 in African-Americans with RA. Unexpectedly, the disease-associated alleles were different in African-Americans than in Europeans. In an effort to better define their contribution, we performed additional SNP genotyping in these genes.
Methods
Seven SNPs were genotyped in 446 African Americans with RA and 733 African American controls. Differences in minor allele frequency between cases and controls were analyzed after controlling for global proportion of European admixture, and pairwise linkage disequilibrium (LD) was estimated among the SNPs.
Results
Three SNPs were significantly associated with RA: TNFAIP3 rs719149 A allele (OR (95% CI) 1.22 (1.03–1.44) (p =0.02); TAGAP rs1738074 G allele OR 0.75 (0.63–0.89), (p =0.0012); and TAGAP rs4709267 G allele 0.74 (0.60–0.91), (p =0.004). Pairwise LD between the TAGAP SNPs was low (R2=0.034). The haplotype containing minor alleles for both TAGAP SNPs was uncommon (4.5%). After conditional analysis on each TAGAP SNP, its counterpart remained significantly associated with RA (rs1738074 for rs4709267 p=0.00001; rs4709267 for rs1738074 p=0.00005), suggesting independent effects.
Conclusions
SNPs in regulatory regions of TAGAP and an intronic SNP (TNFAIP3) are potential susceptibility loci in African Americans. Pairwise LD, haplotype analysis, and SNP conditioning analysis suggest that these two SNPs in TAGAP are independent susceptibility alleles. Additional fine mapping of this gene and functional genomic studies of these SNPs should provide additional insight into the role of these genes in RA.
doi:10.1002/art.33464
PMCID: PMC3299842  PMID: 22127930
3.  An African Ancestry-Specific Allele of CTLA4 Confers Protection against Rheumatoid Arthritis in African Americans 
PLoS Genetics  2009;5(3):e1000424.
Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.
Author Summary
Rheumatoid arthritis (RA) is a systemic autoimmune condition affecting the synovial membranes of diarthrodial joints. The etiology of RA is unclear but is thought to result from an environmental trigger in the context of genetic predisposition. We report that a single nucleotide polymorphism (SNP) (rs231778) in CTLA4, which encodes a negative regulator of T cell activation, is associated (p = 2.4×10−28) with protection from developing RA among African Americans. rs231778 is only polymorphic in populations of African ancestry. Protective alleles such as this one may contribute to the purported lower prevalence of RA in African Americans. Our finding appears to be independent from confounding by linkage with the HLA-DRB1 shared epitope or by genetic admixture. Furthermore, we did not replicate associations of CTLA4 SNPs with RA or other autoimmune diseases previously reported in Asians and Caucasians, such as rs3087243 (+60C/T) and rs231775 (+49A/G). The associations of different SNPs with RA susceptibility specific to different populations highlight the importance of CTLA4 in the pathogenesis of RA and demonstrate the ethnic-specific genetic background that contributes to its susceptibility.
doi:10.1371/journal.pgen.1000424
PMCID: PMC2652071  PMID: 19300490
4.  Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project 
PLoS Genetics  2011;7(2):e1001300.
Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.
Author Summary
To date, most large-scale genome-wide association studies (GWAS) carried out to identify risk factors for complex human diseases and traits have focused on population of European ancestry. It is currently unknown whether the same loci associated with complex diseases and traits in Caucasians will replicate in population of African ancestry. Here, we conducted a large GWAS to identify common DNA polymorphisms associated with coronary heart disease (CHD) and its risk factors (type-2 diabetes, hypertension, smoking status, and LDL- and HDL-cholesterol) in 8,090 African Americans as part of the NHLBI Candidate gene Association Resource (CARe) Project. We replicated 17 associations previously reported in Caucasians, suggesting that the same loci carry common DNA sequence variants associated with CHD and its risk factors in Caucasians and African Americans. At five of these 17 loci, we used the different patterns of linkage disequilibrium between populations of European and African ancestry to identify DNA sequence variants more strongly associated with phenotypes than the index SNPs found in Caucasians, suggesting smaller genomic intervals to search for causal alleles. We also used the CARe data to develop new statistical methods to perform association studies in admixed populations. The CARe Project data represent an extraordinary resource to expand our understanding of the genetics of complex diseases and traits in non-European-derived populations.
doi:10.1371/journal.pgen.1001300
PMCID: PMC3037413  PMID: 21347282
5.  Genome-Wide Association Studies of the PR Interval in African Americans 
PLoS Genetics  2011;7(2):e1001304.
The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10−8) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10−23). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10−16) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.
Author Summary
We performed genome-wide association studies in African American participants from four population-based cohorts to identify genetic variation that correlates with variation in PR interval duration, an electrocardiographic measure of conduction through the atria and atrioventricular node. We observed a strong signal within the gene encoding the cardiac sodium channel, SCN5A, with genome-wide significant association (p<2.5×10−8) in two cohorts and in a meta-analysis of four cohorts with African Americans. We replicated this association in two additional cohorts of African Americans and in Europeans (p = 3×10−16). The signal explains 2% of PR duration variability in African Americans and 0.5% in Europeans. In further meta-analysis, we observed genome-wide significant associations for single nucleotide polymorphisms in SCN10A, MEIS1, TBX5, corresponding to signals observed in people of European and Asian descent. We found an association of genetic ancestry and PR interval in one but not the other three cohorts. Our findings provide the first demonstration of the relevance of these loci to individuals of African ancestry and identify an association signal from SCN5A that is more strongly associated with PR interval in African Americans.
doi:10.1371/journal.pgen.1001304
PMCID: PMC3037415  PMID: 21347284
6.  Genome-wide Ancestry Association Testing Identifies a Common European Variant on 6q14.1 as a Risk Factor for Asthma in African Americans 
Background
Genetic variants that contribute to asthma susceptibility may be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations.
Objective
To identify asthma-associated loci in African Americans.
Methods
We compared local African and European ancestry estimated from dense single nucleotide polymorphism (SNP) genotype data in African American adults with asthma and non-asthmatic controls. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture.
Results
We identified a significant ancestry association peak on chromosomes 6q. Allelic tests for association within this region identified a SNP (rs1361549) on 6q14.1 that was associated with asthma exclusively in African Americans with local European admixture (OR=2.2). The risk allele is common in Europe (42% in the HapMap CEU) but absent in West Africa (0% in the HapMap YRI), suggesting the allele is present in African Americans due to recent European admixture. We replicated our findings in Puerto Ricans and similarly found that the signal of association is largely specific to individuals who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European Americans or in Puerto Ricans in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction.
Conclusion
We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry, and highlight the importance of considering local ancestry in genetic association studies of admixed populations.
doi:10.1016/j.jaci.2012.03.045
PMCID: PMC3503456  PMID: 22607992
asthma; population structure; genome-wide association study; admixture mapping; ancestry association testing; admixed populations; African Americans; Puerto Ricans
7.  Genetic Heterogeneity in Colorectal Cancer Associations in Americans of African vs. European Descent 
Gastroenterology  2010;139(5):1677-1685.e8.
Background & Aims
Genome-wide association studies of colorectal cancer (CRC) have identified risk variants in 10 genomic regions. None of these studies included African Americans, who have the highest incidence and mortality from CRC in the US. For the 10 genomic regions, we performed an association study of Americans of African and European descent.
Methods
We genotyped 22 single nucleotide polymorphisms (SNPs) in DNA samples from 1194 patients with CRC (795 African Americans and 399 European Americans) and 1352 controls (985 African Americans and 367 European Americans). At chromosome 8q24.21 region 3, we analyzed 6 SNPs from 1000 African American cases and 1393 controls. Association testing was done using multivariate logistic regression controlling for ancestry, age, and sex.
Results
Sizes and directions of association for all SNPs tested in European Americans were consistent with previously published studies, but for 9 of 22 SNPs tested in African Americans, they were of an opposite direction. Among African Americans, the SNP rs6983267 at 8q24.21 was not associated with CRC (odds ratio [OR]=1.18; P=0.12); instead, the 8q24.21 SNP rs7014346 (OR=1.15; p=0.03) was associated with CRC in this population. At 15q13.3, rs10318 was associated with CRC in both populations. At 10p14, the opposite allele of rs10795668 was associated with CRC in African Americans (OR=1.35; P=0.04). At 11q23.1, rs3802842 was significantly associated with rectal cancer risk only among African Americans (OR 1.34; P=0.01); this observation was made in previous studies. Among European Americans, SNPs at 8q24.21, 11q23.1, and 16q22.1 were associated with CRC, in agreement with previous reports.
Conclusion
There is genetic heterogeneity in CRC associations in Americans of African vs. European descent.
doi:10.1053/j.gastro.2010.07.038
PMCID: PMC3721963  PMID: 20659471
colon cancer; rectal cancer; ethnicity; genetic polymorphism
8.  Racial or ethnic differences in allele frequencies of single‐nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;65(9):1213-1218.
Background
The anti‐folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis.
Objective
To determine the allele frequencies of five common coding single‐nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African‐Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX.
Methods
Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African‐Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African‐American, as well as 103 normal controls (53 African‐Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes.
Results
Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African‐Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African‐Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African‐Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28‐joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX‐related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African‐Americans, but not in Caucasians.
Conclusions
: These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX‐related adverse events in Caucasians and African‐Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African‐Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.
doi:10.1136/ard.2005.046797
PMCID: PMC1798268  PMID: 16439441
9.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
doi:10.1371/journal.pgen.1004517
PMCID: PMC4125087  PMID: 25102180
PLoS Genetics  2009;5(1):e1000360.
Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.
Author Summary
Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable African or European origin to each region of each such person's chromosomes. Previously, we found a region on chromosome 1 where increased local African ancestry completely accounted for differences in WBC between African and European Americans, suggesting the presence of an African-derived variant causing low WBC. Here, we show that low neutrophil count is predominantly responsible for low WBC; that a dominant, European-derived allele contributes to high neutrophil count; and that the frequency of this allele differs in Africans and Europeans by >91%. Across the chromosome 1 locus, only the well-characterized “Duffy” polymorphism was this differentiated. Neutrophil count was more strongly associated to the Duffy variant than to ancestry, suggesting that the variant itself causes benign ethnic neutropenia. The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.
doi:10.1371/journal.pgen.1000360
PMCID: PMC2628742  PMID: 19180233
PLoS Biology  2013;11(9):e1001661.
A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.
The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
Author Summary
The number of known associations between human diseases and common genetic variants has grown dramatically in the past decade, most being identified in large-scale genetic studies of people of Western European origin. But because the frequencies of genetic variants can differ substantially between continental populations, it's important to assess how well these associations can be extended to populations with different continental ancestry. Are the correlations between genetic variants, disease endpoints, and risk factors consistent enough for genetic risk models to be reliably applied across different ancestries? Here we describe a systematic analysis of disease outcome and risk-factor–associated variants (tagSNPs) identified in European populations, in which we test whether the effect size of a tagSNP is consistent across six populations with significant non-European ancestry. We demonstrate that although nearly all such tagSNPs have effects in the same direction across all ancestries (i.e., variants associated with higher risk in Europeans will also be associated with higher risk in other populations), roughly a quarter of the variants tested have significantly different magnitude of effect (usually lower) in at least one non-European population. We therefore advise caution in the use of tagSNP-based genetic disease risk models in populations that have a different genetic ancestry from the population in which original associations were first made. We then show that this differential strength of association can be attributed to population-dependent variations in the correlation between tagSNPs and the variant that actually determines risk—the so-called functional variant. Risk models based on functional variants are therefore likely to be more robust than tagSNP-based models.
doi:10.1371/journal.pbio.1001661
PMCID: PMC3775722  PMID: 24068893
Introduction
To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.
Methods
Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.
Results
Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score >0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj = 8.08 (95% confidence interval (CI): 1.60-40.89), P = 0.01 and ORadj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01, and ORadj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.
Conclusions
We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.
doi:10.1186/ar2994
PMCID: PMC2911851  PMID: 20444266
PLoS Genetics  2013;9(2):e1003222.
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22–24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ∼1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10−14; odds ratio, 95% confidence interval = 0.82 (0.78–0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10−7; 0.88 (0.84–0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10−8; 0.70 (0.62–0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
Author Summary
African-Americans (AA) are at increased risk of systemic lupus erythematosus (SLE), but the genetic basis of this risk increase is largely unknown. We used admixture mapping to localize disease-causing genetic variants that differ in frequency across populations. This approach is advantageous for localizing susceptibility genes in recently admixed populations like AA. Our genome-wide admixture scan identified seven admixture signals, and we followed the best signal at 2q22–24 with fine-mapping, imputation-based association analysis and experimental validation. We identified two independent coding variants and a non-coding variant within the IFIH1 gene associated with SLE. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
doi:10.1371/journal.pgen.1003222
PMCID: PMC3575474  PMID: 23441136
Importance
Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
Objective
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Results
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
doi:10.1001/jama.2013.2973
PMCID: PMC3667653  PMID: 23571587
PLoS Genetics  2011;7(5):e1001387.
GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10−4) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.
Author Summary
Prostate cancer is one of the most common cancers in men and is especially frequent in men of African origin, as incidence rates in African Americans in the United States are >1.5–fold greater than rates in European Americans. In order to gain a more complete understanding of the genetic basis of inherited susceptibility to prostate cancer in men of African origin, we examined the associations at risk loci identified in men of European and Asian descent in a large African American sample of 3,425 cases of prostate cancer and 3,290 male controls. In testing 49 known risk variants, we were able to demonstrate that at least half of these variants also contribute to risk in African American men. We were able to find additional risk variants in many of the previously reported regions that better captured the pattern of risk in African American men. In addition, we verified and improved upon the evidence we previously reported that there are multiple risk variants in a region of 8q24 that are important in men of African origin.
doi:10.1371/journal.pgen.1001387
PMCID: PMC3102736  PMID: 21637779
PLoS Genetics  2007;3(11):e196.
Hypertension (HTN) is a devastating disease with a higher incidence in African Americans than European Americans, inspiring searches for genetic variants that contribute to this difference. We report the results of a large-scale admixture scan for genes contributing HTN risk, in which we screened 1,670 African Americans with HTN and 387 control individuals for regions of the genome with elevated proportion of African or European ancestry. No loci were identified that were significantly associated with HTN. We also searched for evidence of an admixture signal at 40 candidate genes and eight previously reported linkage peaks, but none appears to contribute substantially to the differential HTN risk between African and European Americans. Finally, we observed nominal association at one of the loci detected in the admixture scan of Zhu et al. 2005 (p = 0.016 at 6q24.3 correcting for four hypotheses tested), although we caution that the significance is marginal and the estimated odds ratio of 1.19 per African allele is less than what would be expected from the original report; thus, further work is needed to follow up this locus.
Author Summary
High blood pressure is more frequent and severe among African Americans than European Americans. To explore whether there are genetic underpinnings to this pattern, we screened the genomes of 1,670 African Americans, searching for loci at which people with hypertension (HTN) have more than the average proportion of African ancestry (eighty percent). We do not detect any region of clearly significant association. In a previous, smaller admixture scan for HTN genes, Zhu and colleagues (2005) reported two regions of association, which we would have expected to replicate if they were as strong as they initially appeared. While we detect marginal evidence of association at one, the signal is very weak, and much weaker than would have been expected from the previous report, so further work is necessary to understand this region. Our results are consistent with there being no common variants with a strong effect accounting for differences in HTN prevalence between African and European Americans. This increases the weight of evidence that non-genetic causes explain most of the difference in rates across populations.
doi:10.1371/journal.pgen.0030196
PMCID: PMC2077893  PMID: 18020707
Arthritis and rheumatism  2012;64(10):10.1002/art.34567.
Objective
African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than SLE patients of European descent. We investigated whether European genetic ancestry protects against the development of lupus nephritis and explored genetic and socioeconomic factors that might explain this effect.
Methods
This was a cross-sectional study of 1906 adults with SLE. Participants were genotyped for 126 single nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. We used logistic regression to test the association between European ancestry and renal disease. Analyses adjusted for continental ancestries, socioeconomic status, and candidate genes.
Results
Participants (n=1906) had on average 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among participants, 34% (n=656) had renal disease. A 10% increase in European ancestry was associated with a 15% reduction in the odds of having renal disease after adjustment for disease duration and sex (OR 0.85, 95% CI 0.82-0.87, p=1.9 × 10−30). Adjusting for other genetic ancestries, measures of socioeconomic status, or SNPs in genes most associated with renal disease (IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), ITGAM (rs9937837) and HLA-DRB1*0301 and DRB1*1501, p<0.05) did not substantively alter this relationship.
Conclusion
European ancestry is protective against the development of renal disease in SLE, an effect independent of other genetic ancestries, common risk alleles, and socioeconomic status.
doi:10.1002/art.34567
PMCID: PMC3865923  PMID: 23023776
Diabetes  2008;57(8):2220-2225.
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— 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 [Pa] = 1.59 × 10−6). Only the intragenic SNP on 11p12 (rs9300039, dominant P [Pd] = 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.
doi:10.2337/db07-1319
PMCID: PMC2494685  PMID: 18443202
Objective
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
Methods
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Results
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
Conclusion
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
doi:10.1002/art.38220
PMCID: PMC4002759  PMID: 24504811
PLoS Genetics  2011;7(6):e1002138.
For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
Author Summary
Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are well known independent risk factors for cardiovascular disease. Lipid-associated genetic variants are being discovered in genome-wide association studies (GWAS) in samples of European descent, but an insufficient amount of data exist in other populations. Therefore, there is a strong need to characterize the effect of these GWAS–identified variants in more diverse cohorts. In this study, we selected over forty genetic loci previously associated with lipid levels and tested for replication in a large European American cohort. We also investigated if the effect of these variants generalizes to non-European descent populations, including African Americans, American Indians, and Mexican Americans/Hispanics. A majority of these GWAS–identified associations replicated in our European American cohort. However, the ability of associations to generalize across other racial/ethnic populations varied greatly, indicating that some of these GWAS–identified variants may not be functional and are more likely to be in linkage disequilibrium with the functional variant(s).
doi:10.1371/journal.pgen.1002138
PMCID: PMC3128106  PMID: 21738485
Human genetics  2011;130(6):807-815.
The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythemathosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry in order to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6×10−5) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2×10−4), rs2071349 (OR = 1.53, p = 1.0×10−3), and rs2844580 (OR = 1.43, p = 1.3×10−3) to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p< 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.
doi:10.1007/s00439-011-1045-2
PMCID: PMC3215804  PMID: 21695597
systemic lupus erythemathosus; African Americans; major histocompatibility complex; single nucleotide polymorphisms
PLoS Genetics  2010;6(4):e1000908.
Retinal vascular caliber provides information about the structure and health of the microvascular system and is associated with cardiovascular and cerebrovascular diseases. Compared to European Americans, African Americans tend to have wider retinal arteriolar and venular caliber, even after controlling for cardiovascular risk factors. This has suggested the hypothesis that differences in genetic background may contribute to racial/ethnic differences in retinal vascular caliber. Using 1,365 ancestry-informative SNPs, we estimated the percentage of African ancestry (PAA) and conducted genome-wide admixture mapping scans in 1,737 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) representing summary measures of retinal arteriolar and venular caliber, respectively, were measured from retinal photographs. PAA was significantly correlated with CRVE (ρ = 0.071, P = 0.003), but not CRAE (ρ = 0.032, P = 0.182). Using admixture mapping, we did not detect significant admixture association with either CRAE (genome-wide score = −0.73) or CRVE (genome-wide score = −0.69). An a priori subgroup analysis among hypertensive individuals detected a genome-wide significant association of CRVE with greater African ancestry at chromosome 6p21.1 (genome-wide score = 2.31, locus-specific LOD = 5.47). Each additional copy of an African ancestral allele at the 6p21.1 peak was associated with an average increase in CRVE of 6.14 µm in the hypertensives, but had no significant effects in the non-hypertensives (P for heterogeneity <0.001). Further mapping in the 6p21.1 region may uncover novel genetic variants affecting retinal vascular caliber and further insights into the interaction between genetic effects of the microvascular system and hypertension.
Author Summary
Retinal vessels provide a window to microvascular systems elsewhere in the body. The diameter of retinal vessels varies between racial/ethnic groups, being generally wider in African Americans compared to European Americans. To determine whether genetic background may contribute to this observed difference, we scanned the entire genomes of 1,737 African Americans, searching for genomic regions where individuals with either wider retinal venular or narrower retinal arteriolar caliber have a difference from the average percentage of African ancestry. We find that the percentage of African ancestry is positively correlated with retinal venular caliber, particularly in the hypertensive individuals. We detect substantive evidence of association between excess African ancestry and wider retinal venular caliber on chromosome 6p21.1 in the hypertensives, but not in the non-hypertensives. The 6p21.1 region contains genes that are known to be involved in development and modulation and of retinal vessels. Our results suggest that genetic factors may contribute to the observed difference in retinal vascular caliber between African Americans and European Americans. Further fine-mapping studies of the genomic region may identify variants affecting retinal vascular caliber.
doi:10.1371/journal.pgen.1000908
PMCID: PMC2855324  PMID: 20419148
Journal of human genetics  2011;56(3):224-229.
Background
A 58kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals.
Methods and Results
Apparently healthy African American siblings (n=548) of patients with documented CAD <60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 SNPs across the 9p21.3 region in a GEE logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time, and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele [G] frequency 0.242), conveyed protection against CAD (OR=0.19, 95% CI: 0.07 to 0.50, p=0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n=990, p=0.024, OR= 0.779, 95% CI: 0.626-0.968).
Conclusions
This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.
doi:10.1038/jhg.2010.171
PMCID: PMC3079521  PMID: 21270820
African American; CDKN2B; Coronary Artery Disease; Genetics; 9p21
Background
Most genome-wide association scans (GWAS) have been carried out in European ancestry populations; no risk variants for breast cancer have been identified solely from African ancestry GWAS data. Few GWAS hits have replicated in African ancestry populations.
Methods
In a nested case-control study of breast cancer in the Black Women’s Health Study (1,199 cases/1,948 controls), we evaluated index SNPs in 21 loci from GWAS of European or Asian ancestry populations, overall, in subtypes defined by estrogen (ER) and progesterone (PR) receptor status (ER+/PR+, n=336; ER−/PR−, n=229), and in triple-negative breast cancer (TNBC, N=81). To evaluate the contribution of genetic factors to population differences in breast cancer subtype, we also examined global percent African ancestry.
Results
Index SNPs in five loci were replicated, including three associated with ER−/PR− breast cancer (TERT rs10069690 in 5p15.33, rs704010 in 10q22.3, and rs8170 in 19p13.11): per allele odds ratios were 1.29 (95% confidence interval (CI) 1.04–1.59), p=0.02, 1.52 (95% CI 1.12–2.08), p=0.01, and 1.30 (95% CI 1.01–1.68), p=0.04, respectively. Stronger associations were observed for TNBC. Furthermore, cases in the highest quintile of percent African ancestry were three times more likely to have TNBC than ER+/PR+ cancer.
Conclusions
These findings provide the first confirmation of the TNBC SNP rs8170 in an African ancestry population, and independent confirmation of the TERT ER− SNP. Further, the risk of developing ER− breast cancer, particularly TNBC, increased with increasing proportion of global African ancestry.
Impact
The findings demonstrate the importance of genetic factors in the disproportionately high occurrence of TNBC in African American women.
doi:10.1158/1055-9965.EPI-12-0769
PMCID: PMC3538887  PMID: 23136140
breast carcinoma; triple-negative; genetic susceptibility; GWAS replication; African-American; SNPs
Inflammatory bowel diseases  2012;18(12):2357-2359.
Background
Crohn’s disease (CD) is highly heritable. NOD2 has emerged as the main susceptibility gene among individuals of European ancestry; however, NOD2 does not appear to contribute to CD susceptibility among many non-European populations. Today’s African American (AA) population represents an admixture of West African (80%) and European (20%) ancestry. Since genotype-based tools are becoming increasingly available for CD, it is important that we validate the risk variants in different populations, such as admixed AAs.
Methods
We analyzed the NOD2 variants among admixed AAs (n=321, 240 with CD and 111 healthy controls) and non-admixed West Africans (n=40) by genotyping for 4 known disease-causing NOD variants. We extracted the publically available 1000 Genomes data on NOD2 variants from 500 subjects of West African origin. Association with disease was evaluated by logistic regression.
Results
An association with CD was found for the classical SNP 1007fs (2.6% CD, 0% HC, p=0.012); there was no association when the genotypic and allelic frequencies of the risk alleles were compared for SNPs R702W and G908R. No known NOD2 risk alleles were seen in either the West African cohort or in subjects of African ancestry from the 1000 Genomes project.
Conclusions
The NOD2 gene is a risk for CD in AAs, although the allele frequencies and the attributable risk are much lower compared to Caucasians. The risk alleles are not seen in the West African population suggesting the risk for CD contributed by NOD2 among AAs is due exclusively to recent European admixture
doi:10.1002/ibd.22944
PMCID: PMC3392535  PMID: 22447396
African Americans; Crohn’s disease; NOD2

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