PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (697891)

Clipboard (0)
None

Related Articles

1.  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
2.  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
3.  FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation 
Human Molecular Genetics  2009;18(9):1692-1703.
Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, Ptrend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.
doi:10.1093/hmg/ddp078
PMCID: PMC2733817  PMID: 19223389
4.  The Autoimmune Disease Risk Allele of UBE2L3 in African American Patients with Systemic Lupus Erythematosus: A Recessive Effect Upon Subphenotypes 
The Journal of Rheumatology  2011;39(1):73-78.
Objective
UBE2L3 is associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis in European ancestry populations, and this locus has not been investigated fully in non-European populations. We studied the UBE2L3 risk allele for association with SLE, interferon-α (IFN-α), and autoantibodies in a predominantly African American SLE cohort.
Methods
We studied 395 patients with SLE and 344 controls. The UBE2L3 rs5754217 polymorphism was genotyped using Taqman primer-probe sets, and IFN-α was measured using a reporter cell assay.
Results
The UBE2L3 rs5754217 T allele was strongly enriched in African American patients with anti-La antibodies as compared to controls, and a recessive model was the best fit for this association (OR 2.55, p = 0.0061). Serum IFN-α also demonstrated a recessive association with the rs5754217 genotype in African American patients, and the TT/anti-La-positive patients formed a significantly high IFN-α subgroup (p = 0.0040). Similar nonstatistically significant patterns of association were observed in the European American patients with SLE. Case-control analysis did not show large allele frequency differences, supporting the idea that this allele is most strongly associated with anti-La-positive patients.
Conclusion
This pattern of recessive influence within a subgroup of patients may explain why this allele does not produce a strong signal in standard case-control studies, and subphenotypes should be included in future studies of UBE2L3. The interaction we observed between UBE2L3 genotype and autoantibodies upon serum IFN-α suggests a biological role for this locus in patients with SLE in vivo.
doi:10.3899/jrheum.110590
PMCID: PMC3304461  PMID: 22045845
SYSTEMIC LUPUS ERYTHEMATOSUS; GENETICS INTERFERON-α; AUTOANTIBODIES; UBE2L3 GENOTYPE
5.  A genome-wide admixture scan identifies MYH9 as a candidate locus associated with non-diabetic end stage renal disease in African Americans 
Nature genetics  2008;40(10):1185-1192.
End stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans. This led to the hypothesis that susceptibility alleles for ESRD have a higher frequency in West African than European gene pool. We performed a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and demonstrated a highly significant association between excess African ancestry and non-diabetic ESRD (LOD 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% credible interval 0.39 – 0.63) compared to African ancestry. Multiple common SNPs (allele frequency ranging from 0.2 to 0.6) in the gene that encodes non-muscle myosin heavy chain type II isoform A (MYH9) were associated with 2-4 times greater risk of non-diabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.
doi:10.1038/ng.232
PMCID: PMC2614692  PMID: 18794854
6.  Analysis and Application of European Genetic Substructure Using 300 K SNP Information 
PLoS Genetics  2008;4(1):e4.
European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.
Author Summary
Ancestry differences corresponding to ethnic groups may be important in determining disease risk factors and optimizing treatment. Our study further defines ancestry relationship among different European ethnic groups by examining over 300 thousand variations in DNA, in over 2,000 individuals. This study allowed a clearer ascertainment of differences that could not be discerned in smaller studies using more limited numbers of DNA variations. We show clear differences among European American participants of different self-identified ethnic affiliation. The analyses showed multiple components of variation. The components showing the largest variations generally corresponded to the grandparental country or region of origin within Europe. We also show the importance of applying this information in determining genetic risk factors for complex diseases. Moreover, the results have enabled a better selection of smaller numbers of DNA variations that can be used in future disease studies to identify more homogenous participant groups and minimize false positive and false negative results in assessing genetic risk factors for disease.
doi:10.1371/journal.pgen.0040004
PMCID: PMC2211544  PMID: 18208329
7.  Analysis and Application of European Genetic Substructure Using 300 K SNP Information 
PLoS Genetics  2008;4(1):e4.
European population genetic substructure was examined in a diverse set of >1,000 individuals of European descent, each genotyped with >300 K SNPs. Both STRUCTURE and principal component analyses (PCA) showed the largest division/principal component (PC) differentiated northern from southern European ancestry. A second PC further separated Italian, Spanish, and Greek individuals from those of Ashkenazi Jewish ancestry as well as distinguishing among northern European populations. In separate analyses of northern European participants other substructure relationships were discerned showing a west to east gradient. Application of this substructure information was critical in examining a real dataset in whole genome association (WGA) analyses for rheumatoid arthritis in European Americans to reduce false positive signals. In addition, two sets of European substructure ancestry informative markers (ESAIMs) were identified that provide substantial substructure information. The results provide further insight into European population genetic substructure and show that this information can be used for improving error rates in association testing of candidate genes and in replication studies of WGA scans.
Author Summary
Ancestry differences corresponding to ethnic groups may be important in determining disease risk factors and optimizing treatment. Our study further defines ancestry relationship among different European ethnic groups by examining over 300 thousand variations in DNA, in over 2,000 individuals. This study allowed a clearer ascertainment of differences that could not be discerned in smaller studies using more limited numbers of DNA variations. We show clear differences among European American participants of different self-identified ethnic affiliation. The analyses showed multiple components of variation. The components showing the largest variations generally corresponded to the grandparental country or region of origin within Europe. We also show the importance of applying this information in determining genetic risk factors for complex diseases. Moreover, the results have enabled a better selection of smaller numbers of DNA variations that can be used in future disease studies to identify more homogenous participant groups and minimize false positive and false negative results in assessing genetic risk factors for disease.
doi:10.1371/journal.pgen.0040004
PMCID: PMC2211544  PMID: 18208329
8.  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
9.  Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry 
Carcinogenesis  2012;33(4):835-840.
Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case–control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04–1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10–1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00–1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.
doi:10.1093/carcin/bgs093
PMCID: PMC3324445  PMID: 22357627
10.  Fine-Mapping in African Americans of Eight Recently Discovered Genetic Loci for Plasma Lipids: The Jackson Heart Study 
Background
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear.
Methods and Results
We genotyped 8 index SNPs and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared to the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, two with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African LD patterns did not assist in narrowing association signals.
Conclusions
We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.
doi:10.1161/CIRCGENETICS.109.914267
PMCID: PMC3074173  PMID: 20570916
lipids; genetics; epidemiology; risk factors
11.  Consistent Directions of Effect for Established Type 2 Diabetes Risk Variants Across Populations 
Diabetes  2012;61(6):1642-1647.
Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (Pheterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.
doi:10.2337/db11-1296
PMCID: PMC3357304  PMID: 22474029
12.  PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes 
PLoS ONE  2013;8(8):e69404.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
doi:10.1371/journal.pone.0069404
PMCID: PMC3737240  PMID: 23950893
13.  Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene 
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
14.  European ancestry and resting metabolic rate in older African Americans 
Background/Objectives
Resting metabolic rate (RMR) contributes 60–80% of total energy expenditure and is consistently lower in populations of African descent compared with populations of European populations. Determination of European ancestry (EA) through SNP analysis would provide an initial step for identifying genetic associations that contribute to low RMR. We sought to evaluate the association between RMR and EA in African Americans.
Subjects/Methods
RMR was measured by indirect calorimetry in 141 African American men and women (aged 74.7 ± 3.0 years) enrolled in a substudy of the Health, Aging and Body Composition Study. Ancestry informative markers were used to estimate individual percent EA. Multivariate regression was used to assess the association between RMR and EA after adjustments for soft tissue fat-free mass (STFFM), fat mass, age, study site, physical activity level and sex.
Results
Mean EA was 23.8 ± 16% (range: 0.1% to 70.7%) and there were no differences by sex. Following adjustments, each percent EA was associated with a 1.6 kcal/day (95% Confidence interval: 0.42, 2.7 kcal/day) higher RMR (p = 0.008). This equates to a 160 kcal/day lower RMR in a population of completely African ancestry with one of completely European ancestry. Additional adjustment for trunk STFFM that partially accounts for high-metabolic rate organs did not affect this association.
Conclusions
European ancestry in African Americans is strongly associated with higher RMR. The data suggest that population differences in RMR may be due to genetic variants.
doi:10.1038/ejcn.2011.22
PMCID: PMC3915864  PMID: 21468093
Admixture; energy metabolism; body composition; genetic mapping
15.  Association of Substance Use Disorders With Childhood Trauma but not African Genetic Heritage in an African American Cohort 
The American journal of psychiatry  2009;166(9):1031-1040.
Objective
Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma.
Method
The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity.
Results
African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76–0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions.
Conclusions
These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.
doi:10.1176/appi.ajp.2009.08071068
PMCID: PMC2768270  PMID: 19605534
16.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
Background
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Methods
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
Results
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
Conclusions
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
doi:10.1016/j.atherosclerosis.2013.02.038
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
17.  Characterizing the admixed African ancestry of African Americans 
Genome Biology  2009;10(12):R141.
Genome-wide SNP analyses reveal the admixed African genetic ancestry of African Americans.
Background
Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.
Results
From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.
Conclusions
These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.
doi:10.1186/gb-2009-10-12-r141
PMCID: PMC2812948  PMID: 20025784
18.  Candidate Gene Association Study of BMI-Related Loci, Weight, and Adiposity in Old Age 
Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)–associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity.
doi:10.1093/gerona/gls227
PMCID: PMC3660116  PMID: 23160366
Obesity; Aging; Genetics; SNPs.
19.  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
20.  A Common Variant in the CDKN2B Gene on Chromosome 9p21 Protects Against Coronary Artery Disease in Americans of African Ancestry 
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
21.  Identification of ATPAF1 as a novel candidate gene for asthma in children 
Background
Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification.
Objective
We sought to identify asthma susceptibility genes in children.
Methods
A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n=116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n=112) and normal controls (n=165). A genomic region containing the ATPAF1 gene was significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in eight independent study populations consisting of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in two consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatics and controls.
Results
Asthma was associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene with two SNPs achieving significance at a genome-wide level (p=2.26×10−5 to 2.2×10−8). Asthma severity was also associated with SNPs and haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the four non-Hispanic populations. Haplotype associations were confirmed in the non-Hispanic populations (p=0.045 to 0.0009). ATPAF1 total RNA expression was significantly (p<0.01) higher in bronchial biopsies from asthmatics than controls.
Conclusion
Genetic variation in the ATPAF1 gene predisposes children of different ancestry to asthma.
doi:10.1016/j.jaci.2011.04.058
PMCID: PMC3185108  PMID: 21696813
asthma; ATPAF1; children; gene; genetic; genome-wide association; purinergic; respiratory; single nucleotide polymorphism; SNP
22.  Self-reported Ethnicity, Genetic Structure and the Impact of Population Stratification in a Multiethnic Study 
Human genetics  2010;128(2):165-177.
It is well-known that population substructure may lead to confounding in case-control association studies. Here, we examined genetic structure in a large racially and ethnically diverse sample consisting of 5 ethnic groups of the Multiethnic Cohort study (African Americans, Japanese Americans, Latinos, European Americans and Native Hawaiians) using 2,509 SNPs distributed across the genome. Principal component analysis on 6,213 study participants, 18 Native Americans and 11 HapMap III populations revealed 4 important principal components (PCs): the first two separated Asians, Europeans and Africans, and the third and fourth corresponded to Native American and Native Hawaiian (Polynesian) ancestry, respectively. Individual ethnic composition derived from self-reported parental information matched well to genetic ancestry for Japanese and European Americans. STRUCTURE-estimated individual ancestral proportions for African Americans and Latinos are consistent with previous reports. We quantified the East Asian (mean 27%), European (mean 27%) and Polynesian (mean 46%) ancestral proportions for the first time, to our knowledge, for Native Hawaiians. Simulations based on realistic settings of case-control studies nested in the Multiethnic Cohort found that the effect of population stratification was modest and readily corrected by adjusting for race/ethnicity or by adjusting for top PCs derived from all SNPs or from ancestry informative markers; the power of these approaches was similar when averaged across causal variants simulated based on allele frequencies of the 2,509 genotyped markers. The bias may be large in case-only analysis of gene by gene interactions but it can be corrected by top PCs derived from all SNPs.
doi:10.1007/s00439-010-0841-4
PMCID: PMC3057055  PMID: 20499252
AIMs; African American; Native Hawaiian; Latino; admixture; principal component analysis
23.  Socioeconomic and Nutritional Factors Account for the Association of Gastric Cancer with Amerindian Ancestry in a Latin American Admixed Population 
PLoS ONE  2012;7(8):e41200.
Gastric cancer is one of the most lethal types of cancer and its incidence varies worldwide, with the Andean region of South America showing high incidence rates. We evaluated the genetic structure of the population from Lima (Peru) and performed a case-control genetic association study to test the contribution of African, European, or Native American ancestry to risk for gastric cancer, controlling for the effect of non-genetic factors. A wide set of socioeconomic, dietary, and clinic information was collected for each participant in the study and ancestry was estimated based on 103 ancestry informative markers. Although the urban population from Lima is usually considered as mestizo (i.e., admixed from Africans, Europeans, and Native Americans), we observed a high fraction of Native American ancestry (78.4% for the cases and 74.6% for the controls) and a very low African ancestry (<5%). We determined that higher Native American individual ancestry is associated with gastric cancer, but socioeconomic factors associated both with gastric cancer and Native American ethnicity account for this association. Therefore, the high incidence of gastric cancer in Peru does not seem to be related to susceptibility alleles common in this population. Instead, our result suggests a predominant role for ethnic-associated socioeconomic factors and disparities in access to health services. Since Native Americans are a neglected group in genomic studies, we suggest that the population from Lima and other large cities from Western South America with high Native American ancestry background may be convenient targets for epidemiological studies focused on this ethnic group.
doi:10.1371/journal.pone.0041200
PMCID: PMC3411699  PMID: 22870209
24.  Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production 
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
25.  Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers 
Carcinogenesis  2013;34(7):1520-1528.
Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11–1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09–1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08–1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1–q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16–1.27; P = 9.7 × 10–16). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.
doi:10.1093/carcin/bgt090
PMCID: PMC3697898  PMID: 23475944

Results 1-25 (697891)