RESUMO
Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.
Assuntos
Cromossomos Humanos Par 21/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , População Branca/genética , Sequenciamento Completo do Genoma/métodos , Criança , Colômbia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , MasculinoRESUMO
INTRODUCTION: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. METHODS: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. RESULTS: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10-6; CYP2A7, p = 7.50 × 10-5; CYP2B6, p = 4.04 × 10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (ß = 0.11, p = 5.58 × 10-4) and controls (ß = 0.12, p = 3.86 × 10-5) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10-4). CONCLUSIONS: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.
Assuntos
Etnicidade/genética , Marcadores Genéticos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumantes/estatística & dados numéricos , Fumar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Hidrocarboneto de Aril Hidroxilases/genética , Estudos de Casos e Controles , Citocromo P-450 CYP2B6/genética , Família 2 do Citocromo P450/genética , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar/efeitos adversos , Fumar/epidemiologia , Estados Unidos/epidemiologia , Proteínas rab4 de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. OBJECTIVE: We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. METHODS: We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. RESULTS: We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. CONCLUSIONS: We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.
Assuntos
Doenças Endêmicas , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Cirrose Hepática/genética , Fígado/patologia , Schistosoma japonicum/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/genética , Adulto , Animais , Brasil/epidemiologia , China/epidemiologia , Doença Crônica , Estudos de Coortes , Progressão da Doença , Feminino , Fibrose , Genótipo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Interleucina-33/metabolismo , Fígado/parasitologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Esquistossomose/complicações , Esquistossomose/epidemiologiaRESUMO
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
Asma/etnologia , Asma/genética , População Negra/genética , Imunoglobulina E/genética , Negro ou Afro-Americano/genética , Algoritmos , Asma/epidemiologia , Barbados , Brasil , Estudos de Casos e Controles , Colômbia , District of Columbia , Predisposição Genética para Doença , Humanos , Imunoglobulina E/sangue , Jamaica , Modelos Estatísticos , Epidemiologia Molecular , New York , Fatores de Risco , População Branca/genéticaRESUMO
BACKGROUND: IL-13 is a signature cytokine of the helper T cell type 2 (TH2) pathway which underlies host defense to helminthic infection and activates production of IgE in both parasitized populations and in urban settings after allergen exposure. METHODOLOGY/PRINCIPAL FINDINGS: Two functional polymorphisms in IL13, rs1800925 (or c.1-1111C>T) and rs20541 (or R130Q) were previously found to be associated with Schistosoma hematobium infection intensity. They have not been thoroughly explored in S. mansoni-endemic populations, however, and were selected along with 5 tagging SNPs for genotyping in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area of Conde, Bahia, in Brazil. Regression models using GEE to account for family membership and family-based quantitative transmission disequilibrium tests (QTDT) were used to evaluate associations with total serum IgE (tIgE) levels and S. mansoni fecal egg counts adjusted for non-genetic covariates. We identified a protective effect for the T allele at rs20541 (Pâ=â0.005) against high S. mansoni egg counts, corroborated by QTDT (Pâ=â0.014). Our findings also suggested evidence for protective effects for the T allele at rs1800925 and A allele at rs2066960 after GEE analysis only (Pâ=â0.050, 0.0002). CONCLUSIONS/SIGNIFICANCE: The two functional variants in IL13 are protective against high S. mansoni egg counts. These markers showed no evidence of association with tIgE levels, unlike tIgE levels previously studied in non-parasitized or atopic study populations.
Assuntos
Interleucina-13/genética , Polimorfismo de Nucleotídeo Único , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/genética , Esquistossomose mansoni/prevenção & controle , Adulto , Animais , Brasil/epidemiologia , Doenças Endêmicas/prevenção & controle , Feminino , Humanos , Imunoglobulina E/sangue , Desequilíbrio de Ligação , Masculino , Esquistossomose mansoni/epidemiologia , Esquistossomose mansoni/imunologia , Células Th2/imunologiaRESUMO
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
População Negra/genética , Negro ou Afro-Americano/genética , População Branca/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/epidemiologiaRESUMO
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
Asma/genética , População Negra/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adulto , Negro ou Afro-Americano/genética , Barbados , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Visceral leishmaniasis (VL) in northeast Brazil is a disease caused by infection with the protozoan Leishmania chagasi. Infection leads to variable clinical outcomes ranging from asymptomatic infection to potentially fatal disease. Prior studies suggest the genetic background of the host contributes to the development of different outcomes after infection, although it is not known if ancestral background itself influences outcomes. VL is endemic in peri-urban areas around the city of Natal in northeast Brazil. The population of northeast Brazil is a mixture of distinct racial and ethnic groups. We hypothesized that some sub-populations may be more susceptible than others to develop different clinical outcomes after L. chagasi infection. Using microsatellite markers, we examined whether admixture of the population as a whole, or markers likely inherited from a distinct ethnic background, differed between individuals with VL, individuals with an asymptomatic infection, or individuals with no infection. There was no apparent significant difference in overall population admixture proportions among the three clinical phenotype groups. However, one marker on Chr. 22 displayed evidence of excess ancestry from putative ancestral populations among different clinical phenotypes, suggesting this region may contain genes determining the course of L. chagasi infection.
Assuntos
Leishmania/fisiologia , Leishmaniose Visceral/etnologia , Leishmaniose Visceral/genética , Animais , Brasil/etnologia , Humanos , Leishmaniose Visceral/parasitologia , Repetições de MicrossatélitesRESUMO
RATIONALE: Asthma prevalence and severity are high among underserved minorities, including those of African descent. The Duffy antigen/receptor for chemokines is the receptor for Plasmodium vivax on erythrocytes and functions as a chemokine-clearing receptor. Unlike European populations, decreased expression of the receptor on erythrocytes is common among populations of African descent, and results from a functional T-46C polymorphism (rs2814778) in the promoter. This variant provides an evolutionary advantage in malaria-endemic regions, because Duffy antigen/receptor for chemokines-negative erythrocytes are more resistant to infection by P. vivax. OBJECTIVES: To determine the role of the rs2814778 polymorphism in asthma and atopy as measured by total serum IgE levels among four populations of African descent (African Caribbean, African American, Brazilian, and Colombian) and a European American population. METHODS: Family-based association tests were performed in each of the five populations to test for association between the rs2814778 polymorphism and asthma or total IgE concentration. MEASUREMENTS AND MAIN RESULTS: Asthma was significantly associated with the rs2814778 polymorphism in the African Caribbean, Colombian, and Brazilian families (P < 0.05). High total IgE levels were associated with this variant in African Caribbean and Colombian families (P < 0.05). The variant allele was not polymorphic among European Americans. CONCLUSIONS: Susceptibility to asthma and atopy among certain populations of African descent is influenced by a functional polymorphism in the gene encoding Duffy antigen/receptor for chemokines. This genetic variant, which confers resistance to malarial parasitic infection, may also partially explain ethnic differences in morbidity of asthma.
Assuntos
Asma/genética , População Negra/genética , Sistema do Grupo Sanguíneo Duffy/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Barbados , Brasil , Estudos de Casos e Controles , Colômbia , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Estados Unidos , População Branca/genéticaRESUMO
BACKGROUND: Evidence of genetic control for total serum IgE (tIgE) level has been reported in multiple populations, although populations with substantial exposure to helminths have yielded lower estimates of heritability, despite evidence suggesting that genes also control a significant portion of the variation in the number of Schistosoma mansoni eggs per gram of fecal matter. METHODS: By use of a whole-population ascertainment scheme, 822 individuals were enrolled from a schistosomiasis-endemic area in Conde, Bahia, in Brazil. Heritability was estimated by using an additive polygenic model, and segregation analysis was performed for 2 quantitative traits, tIgE level and egg count. RESULTS: After adjusting for nongenetic covariates, the heritability of log-transformed tIgE level and log-transformed egg count was estimated at 60% and 31%, respectively. No evidence for a single major gene controlling tIgE level or egg count was observed in segregation analysis for 781 individuals and 403 individuals, respectively, in 318 families, however, which suggests complex biological control. CONCLUSIONS: The high heritability of tIgE level indicates that genetic factors are likely to control tIgE level even in the presence of helminthic infection. Substantial heritability for the burden of S. mansoni infection was confirmed in these Brazilian families. Further genetic studies will be needed to dissect the specific genetic factors that underlie these traits.