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1.
Pediatr Pulmonol ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31496123

RESUMO

Several studies have shown that the airways of asthma patients contain higher diversity of bacteria and are enriched in pathogenic species. However, sampling the airways in children is challenging. Here we aimed to identify differences in the salivary bacterial composition between African Americans children with and without asthma. Saliva samples from 57 asthma cases and 57 healthy controls were analyzed by means of 16S ribosomal RNA amplicon profiling. Measurements of bacterial diversity and genus relative abundance were compared between cases and controls using the nonparametric Wilcoxon test and multivariate regression models. A total of five phyla and a mean of 56 genera were identified. Among them, 15 genera had a relative abundance greater than 1%, being Prevotella, Haemophilus, Streptococcus, and Veillonella the most abundant genera. Differences between cases and controls were found in terms of diversity, as well as in relative abundance for Streptococcus genus (13.0% in cases vs 18.3% in controls; P = .003) and Veillonella genus (11.1% in cases vs 8.0% in controls; P = .002). These differences remained significant after correction for multiple comparisons and when potential confounders were taken into account in logistic regression models. In conclusion, we identified changes in the salivary microbiota associated with asthma among African Americans.

2.
BMC Genet ; 20(1): 59, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315583

RESUMO

BACKGROUND: Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. RESULTS: We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. CONCLUSIONS: Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.

3.
Clin Pharmacol Ther ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31209858

RESUMO

American Thoracic Society guidelines recommend inhaled corticosteroid (ICS) therapy, plus a short-acting bronchodilator, in patients with persistent asthma. However, few prior studies have examined the efficacy of this combination in children of all racial/ethnic groups. We evaluated the association between ICS use and bronchodilator response (BDR) in three pediatric populations with persistent asthma (656 African American, 916 Puerto Rican, and 398 Mexican American children). The association was assessed using multivariable quantile regression. After adjusting for baseline forced expiratory volume in one second and use of controller medications, ICS use was significantly associated with increased BDR only among Mexican Americans (1.56%, P = 0.028) but not African Americans (0.49%, P = 0.426) or Puerto Ricans (0.16%, P = 0.813). Our results demonstrate that ICS augmentation is disproportionate across racial/ethnic groups, where improved BDR is observed in Mexican Americans only. This study highlights the complexities of treating asthma in children, and reinforces the importance of investigating the influence of race/ethnicity on pharmacological response.

4.
Clin Exp Allergy ; 49(6): 789-798, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30697902

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30367910

RESUMO

BACKGROUND: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. OBJECTIVE: We sought to identify genetic predictors of ICS response in multiple population groups with asthma. METHODS: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression. RESULTS: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts). CONCLUSION: We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.

7.
Pharmacogenomics J ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206298

RESUMO

Short-acting ß2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30201514

RESUMO

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

9.
Intensive Care Med Exp ; 6(1): 16, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29987654

RESUMO

BACKGROUND: The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility. METHODS: We first performed a prioritization of candidate genes by integrating our own genomic data from a transcriptomic study in an animal model of ARDS and from the only published genome-wide association study of ARDS study in humans. Then, we selected single nucleotide polymorphisms (SNPs) from prioritized genes to conduct a case-control discovery association study in patients with sepsis-induced ARDS (n = 225) and population-based controls (n = 899). Finally, we validated our findings in an independent sample of 661 sepsis-induced ARDS cases and 234 at-risk controls. RESULTS: Three candidate genes were prioritized: dynein cytoplasmic-2 heavy chain-1, fms-related tyrosine kinase 1 (FLT1), and integrin alpha-1. Of those, a SNP from FLT1 gene (rs9513106) was associated with ARDS in the discovery study, with an odds ratio (OR) for the C allele of 0.76, 95% confidence interval (CI) 0.58-0.98 (p = 0.037). This result was replicated in an independent study (OR = 0.78, 95% CI = 0.62-0.98, p = 0.039), showing consistent direction of effects in a meta-analysis (OR = 0.77, 95% CI = 0.65-0.92, p = 0.003). CONCLUSIONS: We identified FLT1 as a novel ARDS susceptibility gene and demonstrated that integration of genomic data can be a valid procedure to identify novel susceptibility genes. These results contribute to previous firm associations and functional evidences implicating FLT1 gene in other complex traits that are mechanistically linked, through the key role of endothelium, to the pathophysiology of ARDS.

10.
Pharmacogenomics ; 19(8): 707-713, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29785881

RESUMO

Our hypothesis was that children with mutations in genes coding for glutathione S-transferases (GST) have worse asthma outcomes compared with children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three cohorts (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were nonsignificant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.

11.
Am J Respir Crit Care Med ; 197(12): 1552-1564, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29509491

RESUMO

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

12.
Pharmacogenomics ; 18(10): 931-943, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28639505

RESUMO

AIM: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. MATERIALS & METHODS: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. RESULTS: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. CONCLUSION: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.


Assuntos
Antiasmáticos/uso terapêutico , Asma , Farmacogenética/métodos , Variantes Farmacogenômicos , Projetos de Pesquisa , Administração por Inalação , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacocinética , Asma/tratamento farmacológico , Asma/etnologia , Asma/genética , Criança , Grupos de Populações Continentais/genética , Feminino , Genótipo , Humanos , Cooperação Internacional , Masculino , Inquéritos e Questionários , Resultado do Tratamento
13.
Eur Respir J ; 49(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28461288

RESUMO

Puerto Ricans are disproportionately affected with asthma in the USA. In this study, we aim to identify genetic variants that confer susceptibility to asthma in Puerto Ricans.We conducted a meta-analysis of genome-wide association studies (GWAS) of asthma in Puerto Ricans, including participants from: the Genetics of Asthma in Latino Americans (GALA) I-II, the Hartford-Puerto Rico Study and the Hispanic Community Health Study. Moreover, we examined whether susceptibility loci identified in previous meta-analyses of GWAS are associated with asthma in Puerto Ricans.The only locus to achieve genome-wide significance was chromosome 17q21, as evidenced by our top single nucleotide polymorphism (SNP), rs907092 (OR 0.71, p=1.2×10-12) at IKZF3 Similar to results in non-Puerto Ricans, SNPs in genes in the same linkage disequilibrium block as IKZF3 (e.g. ZPBP2, ORMDL3 and GSDMB) were significantly associated with asthma in Puerto Ricans. With regard to results from a meta-analysis in Europeans, we replicated findings for rs2305480 at GSDMB, but not for SNPs in any other genes. On the other hand, we replicated results from a meta-analysis of North American populations for SNPs at IL1RL1, TSLP and GSDMB but not for IL33Our findings suggest that common variants on chromosome 17q21 have the greatest effects on asthma in Puerto Ricans.


Assuntos
Asma/genética , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Asma/etnologia , Criança , Cromossomos Humanos Par 17/genética , Feminino , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Porto Rico/epidemiologia , Adulto Jovem
14.
Sci Rep ; 7: 44548, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28300201

RESUMO

Skin pigmentation is a complex trait that varies largely among populations. Most genome-wide association studies of this trait have been performed in Europeans and Asians. We aimed to uncover genes influencing skin colour in African-admixed individuals. We performed a genome-wide association study of melanin levels in 285 Hispanic/Latino individuals from Puerto Rico, analyzing 14 million genetic variants. A total of 82 variants with p-value ≤1 × 10-5 were followed up in 373 African Americans. Fourteen single nucleotide polymorphisms were replicated, of which nine were associated with skin colour at genome-wide significance in a meta-analysis across the two studies. These results validated the association of two previously known skin pigmentation genes, SLC24A5 (minimum p = 2.62 × 10-14, rs1426654) and SLC45A2 (minimum p = 9.71 × 10-10, rs16891982), and revealed the intergenic region of BEND7 and PRPF18 as a novel locus associated with this trait (minimum p = 4.58 × 10-9, rs6602666). The most significant variant within this region is common among African-descent populations but not among Europeans or Native Americans. Our findings support the advantages of analyzing African-admixed populations to discover new genes influencing skin pigmentation.


Assuntos
Antígenos de Neoplasias/genética , Antiporters/genética , Proteínas de Membrana Transportadoras/genética , Fatores de Processamento de RNA/genética , Pigmentação da Pele/genética , Afro-Americanos/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Pigmentação da Pele/fisiologia
15.
J Allergy Clin Immunol ; 140(2): 571-577, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28069425

RESUMO

BACKGROUND: Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood. METHODS: We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis. RESULTS: CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 (P = 1.5 × 10-12), ACOT7 (P = 2.5 × 10-11), and MND1 (P = 1.4 × 10-9). CONCLUSIONS: In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children.


Assuntos
Asma/sangue , Asma/genética , Metilação de DNA , Hispano-Americanos/genética , Imunoglobulina E/sangue , Leucócitos/metabolismo , Adolescente , Adulto , Asma/imunologia , Criança , Ilhas de CpG , Epigênese Genética , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Adulto Jovem
16.
Elife ; 62017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-28044981

RESUMO

Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both self-identified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2×10-64) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.


Assuntos
Metilação de DNA , Exposição Ambiental , Grupos Étnicos , Hispano-Americanos , Epigênese Genética , Humanos
17.
Eur J Hum Genet ; 25(4): 439-445, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28120837

RESUMO

Several genome-wide association studies have been conducted to investigate the influence of genetic polymorphisms in the development of allergic diseases, but few of them have included the X chromosome. The aim of present study was to perform an X chromosome-wide association study (X-WAS) for asthma symptoms. The study included 1307 children of which 294 were asthma cases. DNA was genotyped using 2.5 HumanOmni Beadchip from Illumina. Statistical analyses were performed in PLINK 1.9, MACH 1.0 and Minimac2. The variant rs12007907 (g.29483892C>A) in IL1RAPL gene was suggestively associated with asthma symptoms in discovery set (odds ratio (OR)=0.49, 95% confidence interval (CI): 0.37-0.67; P=3.33 × 10-6). This result was replicated in the ProAr cohort in men only (OR=0.45, 95% CI: 0.21-0.95; P=0.038). Furthermore, investigating the functional role of the rs12007907 on the production a Th2-type cytokine, IL-13, we found a negative association between the minor allele A with IL-13 production in the discovery set (P=0.044). Gene-based analysis revealed that NUDT10 was the most consistently associated with asthma symptoms in discovery sample. In conclusion, the rs12007907 variant in IL1RAPL gene was negatively associated with asthma and IL-13 production in our study and a sex-specific association was observed in one of the validation samples. It suggests an effect on asthma susceptibility and may explain differences in severe asthma frequency between women and men.


Assuntos
Asma/genética , Proteína Acessória do Receptor de Interleucina-1/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Criança , Feminino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , América Latina , Masculino , Pirofosfatases/genética , Fatores Sexuais
18.
J Asthma ; 54(8): 856-865, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27929698

RESUMO

OBJECTIVE: In the United States, Puerto Ricans and African Americans have lower prevalence of breastfeeding and worse clinical outcomes for asthma compared with other racial/ethnic groups. We hypothesize that the history of breastfeeding is associated with increased forced expiratory volume in 1 second (FEV1) % predicted and reduced asthma exacerbations in Latino and African American youths with asthma. METHODS: As part of the Genes-environments & Admixture in Latino Americans (GALA II) Study and the Study of African Americans, asthma, Genes & Environments (SAGE II), we conducted case-only analyses in children and adolescents aged 8-21 years with asthma from four different racial/ethnic groups: African Americans (n = 426), Mexican Americans (n = 424), mixed/other Latinos (n = 255), and Puerto Ricans (n = 629). We investigated the association between any breastfeeding in infancy and FEV1% predicted using multivariable linear regression; Poisson regression was used to determine the association between breastfeeding and asthma exacerbations. RESULTS: Prevalence of breastfeeding was lower in African Americans (59.4%) and Puerto Ricans (54.9%) compared to Mexican Americans (76.2%) and mixed/other Latinos (66.9%; p < 0.001). After adjusting for covariates, breastfeeding was associated with a 3.58% point increase in FEV1% predicted (p = 0.01) and a 21% reduction in asthma exacerbations (p = 0.03) in African Americans only. CONCLUSION: Breastfeeding was associated with higher FEV1% predicted in asthma and reduced number of asthma exacerbations in African American youths, calling attention to continued support for breastfeeding.


Assuntos
Afro-Americanos/estatística & dados numéricos , Asma/etnologia , Asma/fisiopatologia , Aleitamento Materno/estatística & dados numéricos , Hispano-Americanos , Índice de Massa Corporal , Feminino , Volume Expiratório Forçado , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Fatores Socioeconômicos , Estados Unidos
19.
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
20.
PLoS One ; 11(8): e0157848, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27556405

RESUMO

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is induced in airways by virus and may mediate asthmatic airway remodeling. We sought to evaluate if genetic variants and early life lower respiratory infections jointly affect asthma risk. METHODS: We included Latino children, adolescents, and young adults aged 8-21 years (1736 subjects with physician-diagnosed asthma and 1747 healthy controls) from five U.S. centers and Puerto Rico after excluding subjects with incomplete clinical or genetic data. We evaluated the independent and joint effects of a PAI-1 gain of function polymorphism and bronchiolitis / Respiratory Syncytial Virus (RSV) or other lower respiratory infections (LRI) within the first 2 years of life on asthma risk, asthma exacerbations and lung function. RESULTS: RSV infection (OR 9.9, 95%CI 4.9-20.2) and other LRI (OR 9.1, 95%CI 7.2-11.5) were independently associated with asthma, but PAI-1 genotype was not. There were joint effects on asthma risk for both genotype-RSV (OR 17.7, 95% CI 6.3-50.2) and genotype-LRI (OR 11.7, 95% CI 8.8-16.4). A joint effect of genotype-RSV resulted in a 3.1-fold increased risk for recurrent asthma hospitalizations. In genotype-respiratory infection joint effect analysis, FEV1% predicted and FEV1/FVC % predicted were further reduced in the genotype-LRI group (ß -2.1, 95% CI -4.0 to -0.2; ß -2.0, 95% CI -3.1 to -0.8 respectively). Similarly, lower FEV1% predicted was noted in genotype-RSV group (ß -3.1, 95% CI -6.1 to -0.2) with a trend for lower FEV1/FVC % predicted. CONCLUSIONS: A genetic variant of PAI-1 together with early life LRI such as RSV bronchiolitis is associated with an increased risk of asthma, morbidity, and reduced lung function in this Latino population.


Assuntos
Asma/etiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Infecções Respiratórias/etiologia , Adolescente , Adulto , Alelos , Asma/epidemiologia , Asma/patologia , Asma/fisiopatologia , Estudos de Casos e Controles , Criança , Progressão da Doença , Grupos Étnicos/genética , Feminino , Genótipo , Humanos , Masculino , Razão de Chances , Testes de Função Respiratória , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/patologia , Infecções Respiratórias/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores Socioeconômicos , Estados Unidos/epidemiologia , Adulto Jovem
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