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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.
Gastroenterology ; 156(5): 1496-1507.e7, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30593799

RESUMO

BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. METHODS: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. RESULTS: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. CONCLUSIONS: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Hepacivirus/fisiologia , Hepatite C/genética , Hispano-Americanos/genética , Feminino , Estudo de Associação Genômica Ampla , Hepatite C/diagnóstico , Hepatite C/etnologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucinas/genética , Complexo Principal de Histocompatibilidade/genética , Masculino , Receptores Acoplados a Proteínas-G/genética , Remissão Espontânea , Estados Unidos/epidemiologia , Carga Viral
5.
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.

6.
Hum Mutat ; 39(12): 1973-1979, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30157304

RESUMO

Refractive errors, myopia, and hyperopia are common visual disorders greatly affecting older individuals. Refraction is determined by genetic factors but only a small percentage of its variation has been explained. We performed a genetic association analysis with three ocular phenotypes: spherical equivalent (a continous measure of refraction), axial length, and corneal curvature in 1,871 European-Americans from the Beaver Dam Eye Study. Individuals were genotyped on the Illumina exome array and imputed to the Haplotype Reference Consortium reference panel. After increasing the number of analyzed variants in targeted protein-coding regions 10-fold via imputation, we confirmed associations for two previously known loci with corneal curvature (chr4q12, rs2114039; g.55092626T > C, ß = -0.03 (95% confidence interval [CI]): -0.06, -0.01, P value = 0.01) and spherical equivalent (chr15q14, rs634990; g.35006073T > C, ß = -0.27, 95% CI: -0.45, -0.09, P value = 3.79 × 10-3 ). Despite increased single nucleotide polymorphism (SNP) density, we did not detect any novel significant variants after correction for multiple comparisons. In summary, we confirmed two previous loci associated with corneal curvature and spherical equivalent in a European-American population highlighting the potential biological role of those regions in these traits.

7.
Hum Genet ; 137(4): 281-292, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29637265

RESUMO

Genotype imputation estimates unobserved genotypes from genome-wide makers, to increase genome coverage and power for genome-wide association studies. Imputation has been successful for European ancestry populations in which very large reference panels are available. Smaller subsets of African descent populations are available in 1000 Genomes (1000G), the Consortium on Asthma among African ancestry Populations in the Americas (CAAPA) and the Haplotype Reference Consortium (HRC). We compared the performance of these reference panels when imputing variation in 3747 African Americans (AA) from two cohorts (HCV and COPDGene) genotyped using Illumina Omni microarrays. The haplotypes of 2504 (1000G), 883 (CAAPA) and 32,470 individuals (HRC) were used as reference. We compared the number of variants, imputation quality, imputation accuracy and coverage between panels. In both cohorts, 1000G imputed 1.5-1.6× more variants than CAAPA and 1.2× more than HRC. Similar findings were observed for variants with imputation R2 > 0.5 and for rare, low-frequency, and common variants. When merging imputed variants of the three panels, the total number was 62-63 M with 20 M overlapping variants imputed by all three panels, and a range of 5-15 M variants imputed exclusively with one of them. For overlapping variants, imputation quality was highest for HRC, followed by 1000G, then CAAPA, and improved as the minor allele frequency increased. 1000G, HRC and CAAPA provided high performance and accuracy for imputation of African American individuals, increasing the number of variants available for subsequent analyses. These panels are complementary and would benefit from the development of an integrated African reference panel.

8.
Ann Allergy Asthma Immunol ; 118(4): 483-488.e1, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28284979

RESUMO

BACKGROUND: Allergic asthma is a complex disorder that results from a combination of genetic and environmental factors. Studies suggest that helminth infections can activate a regulatory network characterized by the production of regulatory cytokines, such as interleukin 10 and transforming growth factor ß1 (TGF-ß1) and subsequently protect against immune-mediated diseases, such as asthma. On the other hand, TGF-ß1 is increased in the lungs of individuals with asthma and may modulate airway inflammation. The role of TGF- ß 1 single-nucleotide polymorphisms (SNPs) in allergic disease remains inconclusive. OBJECTIVE: To evaluate the effects of genetic variations in the TGF-ß1 on allergy and helminths infections in children. METHODS: We tested for association among 4 TGF-ß1 SNPs and allergic asthma, specific IgE, skin prick test result, and IL-10 production in 1,335 Brazilians. In addition, we analyzed the association with markers of helminth infection (parasite burden, anti-Ascaris IgE, and worm specific IgG4). The polymorphisms were genotyped using Taq Man probes. RESULTS: We found an association between rs1800470 (C allele) and atopic wheezing (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.37-0.95) and markers of allergy (OR, 0.41; 95% CI, 0.22-0.79). In contrast, a positive association was observed between the haplotype ACCA and Trichuris trichiura infection (OR, 1.85; P = .003) and Ascaris lumbricoides infection (OR, 2.01; P < .001). This haplotype was also associated with increased IL-10 production (ß = 50.7; P < .001). CONCLUSION: Individuals with TGF-ß1 polymorphisms have an increased susceptibility to helminth infections and a lower risk of developing allergy. These studies suggest that immune modulation of allergic disease results not only from environmental factors but also from genetic susceptibility and IL-10 production.


Assuntos
Asma/etiologia , Grupos Étnicos , Predisposição Genética para Doença , Helmintíase/etiologia , Polimorfismo Genético , Fator de Crescimento Transformador beta1/genética , Alelos , Asma/epidemiologia , Brasil/epidemiologia , Brasil/etnologia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Helmintíase/epidemiologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/metabolismo , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Testes Cutâneos
9.
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
10.
Arthritis Rheumatol ; 68(1): 191-200, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26473621

RESUMO

OBJECTIVE: To determine the contribution of rare variants as genetic modifiers of the expressivity, penetrance, and severity of systemic sclerosis (SSc). METHODS: We performed whole-exome sequencing of 78 European American patients with SSc, including 35 patients without pulmonary arterial hypertension (PAH) and 43 patients with PAH. Association testing of case-control probability for rare variants was performed using the unified sequence kernel association test with optimal kernel weighting and small sample adjustment by comparing all SSc patients with a reference population of 3,179 controls from the Exome Sequencing Project 5,500 exome data set. Replication genotyping was performed in an independent sample of 3,263 patients (415 patients with SSc and 2,848 controls). We conducted expression profiling of messenger RNA from 61 SSc patients (19 without PAH and 42 with PAH) and 41 corresponding controls. RESULTS: The ATP8B4 gene was associated with a significant increase in the risk of SSc (P = 2.77 × 10(-7)). Among the 64 ATP8B4 variants tested, a single missense variant, c.1308C>G (F436L, rs55687265), provided the most compelling evidence of association (P = 9.35 × 10(-10), odds ratio [OR] 6.11), which was confirmed in the replication cohort (P = 0.012, OR 1.86) and meta-analysis (P = 1.92 × 10(-7), OR 2.5). Genes involved in E3 ubiquitin-protein ligase complex (ASB10) and cyclic nucleotide gated channelopathies (CNGB3) as well as HLA-DRB5 and HSPB2 (heat-shock protein 27) provided additional evidence of association (P < 10(-5)). Differential ATP8B4 expression was observed among the SSc patients compared to the controls (P = 0.0005). CONCLUSION: ATP8B4 may represent a putative genetic risk factor for SSc and pulmonary vascular complications.


Assuntos
Adenosina Trifosfatases/genética , Hipertensão Pulmonar/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Escleroderma Sistêmico/complicações , Análise de Sequência de DNA
12.
Am J Respir Cell Mol Biol ; 53(2): 226-34, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25514360

RESUMO

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) < P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.


Assuntos
Doença Pulmonar Obstrutiva Crônica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/metabolismo , Locos de Características Quantitativas , Risco , Sarcoglicanas/genética , Sarcoglicanas/metabolismo
13.
Genet Epidemiol ; 37(4): 393-401, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23554133

RESUMO

Characterization of genetic admixture of populations in the Americas and the Caribbean is of interest for anthropological, epidemiological, and historical reasons. Asthma has a higher prevalence and is more severe in populations with a high African component. Association of African ancestry with asthma has been demonstrated. We estimated admixture proportions of samples from six trihybrid populations of African descent and determined the relationship between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 237 ancestry informative markers in asthmatics and nonasthmatic controls from Barbados (190/277), Jamaica (177/529), Brazil (40/220), Colombia (508/625), African Americans from New York (207/171), and African Americans from Baltimore/Washington, D.C. (625/757). We estimated individual ancestries and evaluated genetic stratification using Structure and principal component analysis. Association of African ancestry and asthma and tIgE was evaluated by regression analysis. Mean ± SD African ancestry ranged from 0.76 ± 0.10 among Barbadians to 0.33 ± 0.13 in Colombians. The European component varied from 0.14 ± 0.05 among Jamaicans and Barbadians to 0.26 ± 0.08 among Colombians. African ancestry was associated with risk for asthma in Colombians (odds ratio (OR) = 4.5, P = 0.001) Brazilians (OR = 136.5, P = 0.003), and African Americans of New York (OR: 4.7; P = 0.040). African ancestry was also associated with higher tIgE levels among Colombians (ß = 1.3, P = 0.04), Barbadians (ß = 3.8, P = 0.03), and Brazilians (ß = 1.6, P = 0.03). Our findings indicate that African ancestry can account for, at least in part, the association between asthma and its associated trait, tIgE levels.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/etnologia , Asma/genética , Imunoglobulina E/genética , Afro-Americanos/genética , Algoritmos , Asma/epidemiologia , Barbados , Brasil , Estudos de Casos e Controles , Colômbia , District of Columbia , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Imunoglobulina E/sangue , Jamaica , Modelos Estatísticos , Epidemiologia Molecular , New York , Fatores de Risco
14.
J Allergy Clin Immunol ; 131(6): 1683-90, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23273955

RESUMO

BACKGROUND: Helminth infections are associated with protection against allergies. It is postulated that IL-10 production after helminth infection suppresses skin hypersensitivity and increases IgG4 production, protecting against allergies. OBJECTIVE: We aimed to determine whether IL10 polymorphisms are associated with helminth infection and the risk of wheeze and allergy. METHODS: Twelve IL10 single nucleotide polymorphisms were genotyped in 1353 children aged 4 to 11 years living in a poor urban area in Salvador, Brazil. Wheezing status, Ascaris lumbricoides and Trichuris trichiura infection, IL-10 production by peripheral blood leukocytes stimulated with A lumbricoides extract, serum total IgE levels, specific IgE levels, skin prick test responses to common aeroallergens, and IgG4 and IgE anti-A lumbricoides antibody levels were measured in all children. Association tests were performed by using logistic or linear regression when appropriate, including sex, age, helminth infection, and principal components for ancestry informative markers as covariates by using PLINK. RESULTS: Allele G of marker rs3024496 was associated with the decreased production of IL-10 by peripheral blood leukocytes in response to A lumbricoides stimulation. Allele C of marker rs3024498 was negatively associated with helminth infection or its markers. Marker rs3024492 was positively associated with the risk of atopic wheeze, total IgE levels, and skin prick test responses to cockroach. CONCLUSIONS: Our findings suggest that IL10 polymorphisms might play a role in the production of IL-10, helminth infection, and allergy. We hypothesize that polymorphisms related to protection against helminths, which would offer an evolutionary advantage to subjects in the past, might be associated with increased risk of allergic diseases.


Assuntos
Asma/epidemiologia , Asma/etiologia , Helmintíase/complicações , Interleucina-10/biossíntese , Interleucina-10/genética , Polimorfismo Genético , Sons Respiratórios/etiologia , Adolescente , Alelos , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Ordem dos Genes , Ligação Genética , Genótipo , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , População Urbana
15.
Hum Genet ; 132(1): 79-90, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22986903

RESUMO

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.


Assuntos
Anquirinas/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Pulmão/fisiopatologia , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Anquirinas/metabolismo , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 14/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade
16.
Am J Phys Anthropol ; 143(1): 13-20, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20734436

RESUMO

Colombia is a country with great geographic heterogeneity and marked regional differences in pre-Columbian native population density and in the extent of past African and European immigration. As a result, Colombia has one of the most diverse populations in Latin America. Here we evaluated ancestry in over 1,700 individuals from 24 Colombian populations using biparental (autosomal and X-Chromosome), maternal (mtDNA), and paternal (Y-chromosome) markers. Autosomal ancestry varies markedly both within and between regions, confirming the great genetic diversity of the Colombian population. The X-chromosome, mtDNA, and Y-chromosome data indicate that there is a pattern across regions indicative of admixture involving predominantly Native American women and European and African men.


Assuntos
Grupos de Populações Continentais/genética , Marcadores Genéticos/genética , Genética Populacional/métodos , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Colômbia , DNA Mitocondrial/genética , Feminino , Geografia , Haplótipos/genética , Humanos , Masculino , Fatores Sexuais
17.
J Lipid Res ; 51(9): 2766-74, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20562440

RESUMO

Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 x 10(-7) - 1.7 x 10(-8)) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the omega-6 series (P = 2.11 x 10(-13) - 1.8 x 10(-20)). The minor allele across all SNPs was consistently associated with decreased omega-6 PUFAs, with the exception of dihomo-gamma-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Delta-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA.


Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Ômega-6/metabolismo , Genética Populacional , Geografia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Pessoa de Meia-Idade , Família Multigênica
18.
Int Arch Allergy Immunol ; 152(1): 32-40, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19940503

RESUMO

BACKGROUND: A disintegrin and metalloprotein-33 (ADAM33) participates in the bronchial remodeling process in asthma, and genetic analyses pointed it out as a candidate gene in asthma. METHODS: To analyze the association between ADAM33 and asthma and total and mite-specific IgE levels in a population of the Caribbean Coast of Colombia, we genotyped 6 single-nucleotide polymorphisms of ADAM33 in 429 asthmatics, 401 controls and 116 family trios using fluorogenic probes. Total and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus were determined by ELISA. Case-control and family-based analyses were performed. Case-control association analyses were corrected by population stratification using a set of 52 ancestry-informative markers. RESULTS: Eight common haplotypes were identified; among them, H4 (GCAGGG) was associated with asthma in the family group (Z score: -2.049, p = 0.04). We also found an association between the TT genotype of ST+7 and asthma in the case-control study (p = 0.05) that disappeared after correcting for multiple testing. In the family-based analysis, this genotype was a risk factor for asthma (p = 0.01), high total IgE (Z score: 2.546, p = 0.01) and high specific IgE against B. tropicalis (p = 0.02) and D. pteronyssinus (Z score: 2.414, p = 0.01). V4 was associated with specific IgE against B. tropicalis (p = 0.03); T2 with asthma (p = 0.03), high total IgE (p = 0.02) and IgE against D. pteronyssinus (p = 0.03) and T1 with high total IgE (p = 0.04). None of these associations was maintained after correction for multiple testing. CONCLUSIONS: Our findings suggest a relevant role of ADAM33 in thepathogenesis of asthma in this population.


Assuntos
Proteínas ADAM/genética , Asma/genética , Predisposição Genética para Doença , Haplótipos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alérgenos/imunologia , Animais , Asma/epidemiologia , Estudos de Casos e Controles , Colômbia/epidemiologia , Dermatophagoides pteronyssinus/imunologia , Feminino , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Ácaros/imunologia , Adulto Jovem
19.
J Allergy Clin Immunol ; 125(2): 336-346.e4, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19910028

RESUMO

BACKGROUND: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Asma/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adulto , Afro-Americanos/genética , Barbados , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
Int Arch Allergy Immunol ; 151(3): 237-46, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19786804

RESUMO

BACKGROUND: The C-509T polymorphism of the transforming growth factor beta-1 (TGFB1) gene has been associated with asthma and asthma-related phenotypes, but its influence on total and specific IgE levels is controversial. OBJECTIVE: To investigate the association between C-509T and asthma, as well as total IgE and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus, in a Colombian population. METHODS: The study population consisted of 417 asthmatics, 390 controls and 116 nuclear families. The C-509T polymorphism was genotyped using single-base extension minisequencing or Taq Man probes. IgE and TGFbeta1 levels were measured by ELISA. Regression analysis and family-based association tests were performed in cases/controls and families. Associations were corrected by population structure using a panel of 52 ancestry informative markers in the case-control dataset. RESULTS: There was no association between C-509T and asthma. In asthmatics, the CC genotype was associated with higher total IgE levels compared with the other genotypes [mean IgE: 2.81 +/- 0.42 vs. 2.71 +/- 0.45 log IU/ml; p = 0.016, corrected p value (p(c)) = 0.019]. When only atopic asthmatics were included, the significance remained (p = 0.02, p(c) = 0.03). In the family-based analyses, the C allele was associated with higher total IgE levels (p = 0.02) and the CC genotype with specific IgE to D. pteronyssinus (p = 0.01). CONCLUSIONS: C-509T is associated with total IgE levels and specific IgE to D. pteronyssinus in asthmatic patients. In contrast to other studies, we found the CC genotype to be associated with higher levels of total and specific IgE. Differences in the frequency of this allele among populations could alter its effects as a risk factor for asthma-associated phenotypes.


Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Imunoglobulina E/sangue , Polimorfismo de Nucleotídeo Único/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Animais , Antígenos de Dermatophagoides/imunologia , Asma/sangue , Asma/imunologia , Estudos de Casos e Controles , Colômbia , Dermatophagoides pteronyssinus/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Fator de Crescimento Transformador beta1/sangue
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