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2.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
4.
Nat Genet ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30455414

RESUMO

We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic.

5.
J Asthma ; 54(1): 1-8, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27177148

RESUMO

OBJECTIVE: Transferability of significantly associated loci or GWAS "hits" adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. METHODS: Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an "exact" approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a "local" approach that examined all the regional SNPs in LD with the index SNP. RESULTS: Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], P = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149-4.013], P = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected P values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of IL33 were significantly associated with asthma. CONCLUSIONS: This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the IL33, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding.


Assuntos
Afro-Americanos/genética , Asma/genética , Adulto , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
6.
Nat Commun ; 7: 12522, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27725671

RESUMO

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Genoma Humano , Migração Humana , Sequência de Bases , DNA Intergênico/genética , Feminino , Heterogeneidade Genética , Geografia , Humanos , Masculino , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sexismo
7.
Anticancer Res ; 35(5): 2565-70, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25964531

RESUMO

BACKGROUND/AIM: Prostate cancer (PCa) shows disproportionately higher incidence and disease-associated mortality in African Americans. The human crystallin beta B2 (CRYBB2) gene has been reported as one tumor signature gene differentially expressed between African American and European American cancer patients. We investigated the role of CRYBB2 genetic variants in PCa in African Americans. MATERIALS AND METHODS: Subjects comprised of 233 PCa cases and 294 controls. Nine haplotype-tagged single nucleotide polymorphisms (SNPs) in and around the CRYBB2 gene were genotyped by pyrosequencing. Association analyses were performed for PCa with adjustment for age and prostate-specific antigen (PSA), under an additive genetic model. RESULTS: Out of the nine SNPs examined, rs9608380 was found to be nominally associated with PCa (odds ratio (OR)=2.619 (95% confidence interval (CI)=1.156-5.935), p=0.021). rs9306412 was in strong linkage disequilibrium with rs9608380 that showed an association p-value of 0.077. Using ENCODE data, we found rs9608380 mapped to a region annotated with regulatory motifs, such as DNase hypersensitive sites and histone modifications. CONCLUSION: This is the first study to analyze the association between genetic variations in the CRYBB2 gene with PCa. rs9608380, associated with PCa, is a potentially functional variant.


Assuntos
Neoplasias da Próstata/genética , Cadeia B de beta-Cristalina/genética , Adulto , Idoso , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/genética , Neoplasias da Próstata/patologia , Fatores de Risco
8.
J Hypertens ; 29(10): 1906-12, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21881522

RESUMO

OBJECTIVE: Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African-Americans. METHODS: We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African-Americans and performed a case-control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components). RESULTS: A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10) and rs4657251 in the RGS5 gene (P = 9.7 × 10) were the top hits. Effect size for each of these variants was approximately 2-3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01). CONCLUSION: These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.


Assuntos
Afro-Americanos/genética , Pressão Sanguínea/genética , Selectina E/genética , Hipertensão/genética , Proteínas RGS/genética , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Cromossomos Humanos Par 1/genética , Estudos de Coortes , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
Nat Genet ; 43(9): 887-92, 2011 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-21804549

RESUMO

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.


Assuntos
Asma/etnologia , Asma/genética , Loci Gênicos , Predisposição Genética para Doença , Afro-Americanos/genética , Asma/epidemiologia , Região do Caribe/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , América do Norte/etnologia , Risco
10.
Genet Epidemiol ; 34(6): 561-8, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20717976

RESUMO

Admixture is a potential source of confounding in genetic association studies, so it becomes important to detect and estimate admixture in a sample of unrelated individuals. Populations of African descent in the US and the Caribbean share similar historical backgrounds but the distributions of African admixture may differ. We selected 416 ancestry informative markers (AIMs) to estimate and compare admixture proportions using STRUCTURE in 906 unrelated African Americans (AAs) and 294 Barbadians (ACs) from a study of asthma. This analysis showed AAs on average were 72.5% African, 19.6% European and 8% Asian, while ACs were 77.4% African, 15.9% European, and 6.7% Asian which were significantly different. A principal components analysis based on these AIMs yielded one primary eigenvector that explained 54.04% of the variation and captured a gradient from West African to European admixture. This principal component was highly correlated with African vs. European ancestry as estimated by STRUCTURE (r(2)=0.992, r(2)=0.912, respectively). To investigate other African contributions to African American and Barbadian admixture, we performed PCA on approximately 14,000 (14k) genome-wide SNPs in AAs, ACs, Yorubans, Luhya and Maasai African groups, and estimated genetic distances (F(ST)). We found AAs and ACs were closest genetically (F(ST)=0.008), and both were closer to the Yorubans than the other East African populations. In our sample of individuals of African descent, approximately 400 well-defined AIMs were just as good for detecting substructure as approximately 14,000 random SNPs drawn from a genome-wide panel of markers.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Algoritmos , Barbados/epidemiologia , Região do Caribe/epidemiologia , Estudos de Casos e Controles , Frequência do Gene , Genética Populacional , Genótipo , Haplótipos , Humanos , Cadeias de Markov , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
11.
BMC Genomics ; 11: 417, 2010 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-20602785

RESUMO

BACKGROUND: Admixture mapping is a powerful approach for identifying genetic variants involved in human disease that exploits the unique genomic structure in recently admixed populations. To use existing published panels of ancestry-informative markers (AIMs) for admixture mapping, markers have to be genotyped de novo for each admixed study sample and samples representing the ancestral parental populations. The increased availability of dense marker data on commercial chips has made it feasible to develop panels wherein the markers need not be predetermined. RESULTS: We developed two panels of AIMs (approximately 2,000 markers each) based on the Affymetrix Genome-Wide Human SNP Array 6.0 for admixture mapping with African American samples. These two AIM panels had good map power that was higher than that of a denser panel of approximately 20,000 random markers as well as other published panels of AIMs. As a test case, we applied the panels in an admixture mapping study of hypertension in African Americans in the Washington, D.C. metropolitan area. CONCLUSIONS: Developing marker panels for admixture mapping from existing genome-wide genotype data offers two major advantages: (1) no de novo genotyping needs to be done, thereby saving costs, and (2) markers can be filtered for various quality measures and replacement markers (to minimize gaps) can be selected at no additional cost. Panels of carefully selected AIMs have two major advantages over panels of random markers: (1) the map power from sparser panels of AIMs is higher than that of approximately 10-fold denser panels of random markers, and (2) clusters can be labeled based on information from the parental populations. With current technology, chip-based genome-wide genotyping is less expensive than genotyping approximately 20,000 random markers. The major advantage of using random markers is the absence of ascertainment effects resulting from the process of selecting markers. The ability to develop marker panels informative for ancestry from SNP chip genotype data provides a fresh opportunity to conduct admixture mapping for disease genes in admixed populations when genome-wide association data exist or are planned.


Assuntos
Afro-Americanos/genética , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/etnologia , Hipertensão/genética , Análise de Sequência com Séries de Oligonucleotídeos
12.
Life Sci ; 86(5-6): 153-7, 2010 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-19958777

RESUMO

AIMS: We tested the hypothesis that body fat percentage determines cardiac sympathovagal balance in healthy subjects. MAIN METHODS: Heart rate variability (HRV) measurements were made of the standard deviation of the normal-normal RR intervals (SDNN) and the low frequency/high frequency (LF/HF) ratio, from time domain and fast Fourier transform spectral analysis of electrocardiogram RR intervals during trials of uncontrolled and controlled (paced) breathing at 0.2Hz. Body fat percentage was measured by dual energy x-ray absorptiometric (DEXA) scanning. Significance of differences between uncontrolled and controlled (paced) breathing was determined by analysis of variance and correlations between body fat percentage and HRV measurements by Pearson's coefficient at P<0.05. KEY FINDINGS: Percent body fat was negatively correlated with LF/HF during the uncontrolled breathing (r=-0.56, two-tailed P<0.05, one-tailed P<0.01) but not during the paced breathing trial (r=-0.34, (P>0.1). SIGNIFICANCE: We conclude that sympathetic activity produced by paced breathing at 0.2Hz can obscure the relationship between body fat percentage and sympathovagal balance and that high body fat percentage may be associated with low sympathetic modulation of the heart rate in healthy adolescent/young adult males.


Assuntos
Tecido Adiposo/anatomia & histologia , Adiposidade/fisiologia , Frequência Cardíaca/fisiologia , Sistema Nervoso Simpático/fisiologia , Nervo Vago/fisiologia , Absorciometria de Fóton , Tecido Adiposo/metabolismo , Adulto , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Eletrocardiografia , Metabolismo Energético/fisiologia , Jejum/metabolismo , Jejum/fisiologia , Análise de Fourier , Humanos , Masculino , Taxa Respiratória/fisiologia , Adulto Jovem
13.
Genes Chromosomes Cancer ; 41(1): 2017 Apr, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15236317

RESUMO

Loss of the short arm of chromosome 1 is frequently observed in many tumor types, including melanoma. We recently localized a third melanoma susceptibility locus to chromosome band 1p22. Critical recombinants in linked families localized the gene to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely we have performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. Eighty percent of familial melanomas exhibited loss of heterozygosity (LOH) within the region, with a smallest region of overlapping deletions (SRO) of 9 Mb between D1S207 and D1S435. This high frequency of LOH makes it very likely that the susceptibility locus is a tumor suppressor. In sporadic tumors, four SROs were defined. SRO1 and SRO2 map within the critical recombinant and familial tumor region, indicating that one or the other is likely to harbor the susceptibility gene. However, SRO3 may also be significant because it overlaps with the markers with the highest 2-point LOD score (D1S2776), part of the linkage recombinant region, and the critical region defined in mesothelioma. The candidate genes PRKCL2 and GTF2B, within SRO2, and TGFBR3, CDC7, and EVI5, in a broad region encompassing SRO3, were screened in 1p22-linked melanoma kindreds, but no coding mutations were detected. Allelic loss in melanoma cell lines was significantly less frequent than in fresh tumors, indicating that this gene may not be involved late in progression, such as in overriding cellular senescence, necessary for the propagation of melanoma cells in culture.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Genes Supressores de Tumor , Predisposição Genética para Doença , Melanoma/genética , Sequência de Bases , Ligação Genética , Genótipo , Humanos , Escore Lod , Perda de Heterozigosidade , Deleção de Sequência
14.
Gene ; 284(1-2): 203-13, 2002 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-11891061

RESUMO

In silico gene identification from finished and unfinished human genome sequence has become critically important in many projects seeking to gain insights into the gene content of genomic regions implicated in diseases. To establish limitations and criteria for in silico gene identification, and to identify novel genes of potential relevance to human prostate cancer and melanoma, 3 Mb of chromosome 1 sequence have been analyzed using GeneMachine. This program is a software suite comprising of sequence similarity programs and four gene identification programs. A total of 49 potential transcripts were selected and 37 of them were selected for experimental validation. We verified 16 of the predicted genes by experimental analysis. The comparison of the predicted transcripts with their cloned forms helped to refine predicted gene models as well as to identify splice variants for several of them. Although sequences matching with ten of our verified genes have been recently deposited in the GenBank, six of them remain novel. Our studies support the feasibility of identifying novel genes from regions of interest using draft human genome sequence.


Assuntos
Genes/genética , Software , Cromossomos Humanos Par 1/genética , Clonagem Molecular , DNA/química , DNA/genética , DNA Complementar/química , DNA Complementar/genética , Éxons/genética , Feminino , Expressão Gênica , Genoma Humano , Humanos , Masculino , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de DNA
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