Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
1.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1177-1186, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31142495

RESUMO

BACKGROUND: Previous studies associated night-shift work with melatonin disruption, with mixed evidence regarding the modulating effects of chronotype (i.e., diurnal preference). METHODS: One hundred and thirty active nurses (84 rotating-shift and 46 day-shift workers) in the Nurses' Health Study II wore a head-mounted light meter and collected spontaneous urine voids over 3 days. 6-Sulfatoxymelatonin (aMT6s), the major urinary metabolite of melatonin, was assessed. RESULTS: Rotating-shift workers on night shifts had more light exposure and lower urinary melatonin levels during the night, and urinary melatonin rhythms with smaller peaks [11.81 ng/mg-creatinine/h, 95% confidence interval (CI), 9.49-14.71 vs. 14.83 ng/mg-creatinine/h, 95% CI, 11.72-18.75] and later peak onset (5.71 hours, 95% CI, 4.76-6.85 vs. 4.10 hours, 95% CI, 3.37-4.99), compared with day-shift workers. Furthermore, evening chronotypes' melatonin rhythms had later peak onset compared with morning types (4.90 hours, 95% CI, 3.94-6.09 vs. 3.64 hours, 95% CI, 2.99-4.43). However, among day-shift workers, morning chronotypes had melatonin rhythms with greater mean levels, larger peaks, and earlier peak onset compared with evening chronotypes; patterns were similar comparing evening versus morning chronotypes among rotating-shift workers on night shifts. The interaction of rotating-shift work and chronotype was significant across all parameters (P < 0.05). CONCLUSIONS: As expected, rotating-shift workers on night shifts had greater light exposure and lower urinary melatonin levels during the night compared with day-shift workers. Intriguingly, melatonin rhythms were dependent on both chronotype and rotating-shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythms. IMPACT: The joint effects of shift-work type and chronotype require attention in future studies.

2.
Am J Epidemiol ; 188(4): 760-767, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649161

RESUMO

Gene-environment (G × E) interaction is important for many complex traits. In a case-control study of a disease trait, logistic regression is the standard approach used to model disease as a function of a gene (G), an environmental factor (E), G × E interaction, and adjustment covariates. We propose an alternative model with G as the outcome and show how it provides a unified framework for obtaining results from all of the common G × E tests. These include the 1-degree-of-freedom (df) test of G × E interaction, the 2-df joint test of G and G × E, the case-only and empirical Bayes tests, and several 2-step tests. In the context of this unified model, we propose a novel 3-df test and demonstrate that it provides robust power across a wide range of underlying G × E interaction models. We demonstrate the 3-df test in a genome-wide scan of G × sex interaction for childhood asthma using data from the Children's Health Study (Southern California, 1993-2001). This scan identified a strong G × sex interaction at the phosphodiesterase gene 4D locus (PDE4D), a known asthma-related locus, with a strong effect in males (per-allele odds ratio = 1.70; P = 3.8 × 10-8) and virtually no effect in females. We describe a software program, G×EScan (University of Southern California, Los Angeles, California), which can be used to fit standard and unified models for genome-wide G × E studies.

3.
Obesity (Silver Spring) ; 26(12): 1938-1948, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30358166

RESUMO

OBJECTIVE: Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity. METHODS: Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult). RESULTS: A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05). CONCLUSIONS: The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity.

4.
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.

6.
Nat Genet ; 50(8): 1072-1080, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013184

RESUMO

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

7.
Ophthalmol Retina ; 2(2): 96-105, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29503969

RESUMO

Objective: To identify factors associated with prevalent diabetic retinopathy (DR) among Chinese American adults with type 2 diabetes mellitus (T2DM), and to compare these factors to ones previously described for a population-based sample of Latinos with a higher DR prevalence. Design: Population-based cross-sectional study. Participants: 4582 Chinese Americans aged 50 or older residing in Monterey Park, California. Methods: Participants completed an in-home questionnaire on socio-demographic status and medical history, and a comprehensive clinical eye examination, using the same protocol implemented in the Los Angeles Latino Eye Study. Fundus photographs from 7 Early Treatment Diabetic Retinopathy fields were graded in a masked manner using a modified Airlie House grading system to assess presence and severity of DR. Logistic regression analyses based on a conceptual model of DR risk identified factors associated with prevalent DR. Main Outcome Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with DR and vision-threatening DR (VTDR). Results: In total, 238 participants were diagnosed with any DR; 27 of these were classified as having VTDR. Both, any DR and VTDR showed statistically significant positive associations with T2DM duration (OR5-9 years = 1.24, OR10-14 years = 2.07, OR15+years = 3.99), glycosylated hemoglobin (HbA1c) (OR6.5-6.9% = 1.33, OR7-7.9% = 1.86, OR8%+ = 3.22), systolic blood pressure (SBP) (ORper 10mmHg+ = 1.19), and insulin treatment (ORinsulin+ = 2.44). For VTDR, we also found novel associations with antihypertensive drugs (OR: 0.18; 95% CI: 0.06-0.61) and statins (OR: 4.96; 95% CI: 1.60-16.41). Chinese Americans and Latinos had a nearly identical DR probability based on HbA1c and SBP. However, Latinos had a higher DR probability at every year of duration of T2DM (≥ 5 years). Conclusions: While we observed an overall lower DR prevalence in Chinese Americans than in Latinos (35.8% of individuals with TD2M in Chinese Americans versus 42.0% in Latinos), our data indicate that the impact of increasing HbA1c and SBP on DR probability is incrementally the same in both populations. However, increasing T2DM duration is associated with higher DR probability in Latinos than Chinese Americans, even after controlling for other known predictors. Novel factors associated with VTDR include antihypertensive drugs and statins. However, to determine if these drugs impact VTDR susceptibility, we need longitudinal data and more cases.

9.
Cancer Prev Res (Phila) ; 11(2): 93-102, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29118161

RESUMO

Lung cancer gene methylation detected in sputum assesses field cancerization and predicts lung cancer incidence. Hispanic smokers have higher lung cancer susceptibility compared with non-Hispanic whites (NHW). We aimed to identify novel dietary nutrients affecting lung cancer gene methylation and determine the degree of ethnic disparity in methylation explained by diet. Dietary intakes of 139 nutrients were assessed using a validated Harvard food frequency questionnaire in 327 Hispanics and 1,502 NHWs from the Lovelace Smokers Cohort. Promoter methylation of 12 lung cancer genes was assessed in sputum DNA. A global association was identified between dietary intake and gene methylation (Ppermutation = 0.003). Seventeen nutrient measurements were identified with magnitude of association with methylation greater than that seen for folate. A stepwise approach identified B12, manganese, sodium, and saturated fat as the minimally correlated set of nutrients whose optimal intakes could reduce the methylation by 36% (Ppermutation < 0.001). Six protective nutrients included vitamin D, B12, manganese, magnesium, niacin, and folate. Approximately 42% of ethnic disparity in methylation was explained by insufficient intake of protective nutrients in Hispanics compared with NHWs. Functional validation of protective nutrients showed an enhanced DNA repair capacity toward double-strand DNA breaks, a mechanistic biomarker strongly linked to acquisition of lung cancer gene methylation in smokers. Dietary intake is a major modifiable factor for preventing promoter methylation of lung cancer genes in smokers' lungs. Complex dietary supplements could be developed on the basis of these protective nutrients for lung cancer chemoprevention in smokers. Hispanic smokers may benefit the most from this complex for reducing their lung cancer susceptibility. Cancer Prev Res; 11(2); 93-102. ©2017 AACR.

10.
Am J Epidemiol ; 187(1): 45-52, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28605396

RESUMO

We examined traffic-related pollution (TRP) exposure and respiratory health effects in Hispanic white (HW) children, both compared with non-Hispanic white (NHW) children and according to genetically determined Native American (NA) ancestry. The sample included over 5,000 children from the Children's Health Study in California, followed during 1993-2014. HW children were 1.47 (95% confidence interval (CI): 1.24, 1.73) times more likely to live close (<500 m) to a freeway and 1.54 (95% CI: 1.26, 1.87) times more likely to live close (<75 m) to a major nonfreeway road compared with NHW children. Among HW children, those with >50% NA ancestry were >40% more likely to live close to a freeway or to a major nonfreeway road, compared with those with ≤50% NA ancestry. The association of TRP with ever having been diagnosed by a doctor as having asthma differed between HW and NHW children (P < 0.05), with the strongest association among HW children with >50% NA ancestry. Within this subgroup, those close to a major nonfreeway road were 2.16 (95% CI: 1.26, 3.69) times more likely to have ever reported asthma compared with those living further away. This paper provides evidence that HW children in southern California, especially those with greater NA ancestry, are more exposed to TRP and are potentially at greater risk for TRP-related respiratory health effects.

11.
Ophthalmol Retina ; 2(3): 209-216, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-31047588

RESUMO

OBJECTIVE: To assess associations between age-related macular degeneration (AMD) and multiple factors comprising a conceptual model of AMD risk in a population of Chinese Americans, and to draw comparisons with a similar risk assessment of a Latino population. DESIGN: A cross-sectional population-based study. PARTICIPANTS: We enrolled 4582 Chinese Americans aged ≥50 residing in Monterey Park, California. METHODS: Participants completed a comprehensive eye examination, including stereoscopic fundus photography and ocular biometric measurements. Fundus images were graded using a modified version of the Wisconsin Age-Related Maculopathy Grading System. MAIN OUTCOMES AND MEASURES: Odds ratios for factors significantly modifying the risk of AMD and its related retinal lesions. RESULTS: Of the eligible participants, 4172 (72%) had fundus photographs gradable for AMD. Early AMD was present in 375 eyes (4.6%), and late AMD was present in 17 (0.2%). Shorter axial length, male sex, older age, and family history of AMD were identified as independent risk factors for prevalent AMD and its characteristic retinal lesions using a conceptual model of potential AMD risk factors. Of 4 AMD risk factors identified for Latinos, 3 (older age, male sex, shorter axial length) overlapped with those identified for Chinese Americans, with an association similar in magnitude and direction. Lower levels of education were a risk factor specific to Latinos. Based on a multivariable logistic regression model, the predicted probability of early AMD was 31% lower among Chinese Americans relative to Latinos (95% confidence interval [CI], 17%-43%). Chinese Americans also had statistically significantly lower odds of any AMD and 2 types of early retinal lesions symptomatic of AMD. CONCLUSIONS: Factors associated with prevalent AMD are similar for Chinese Americans and Latinos. Chinese Americans who were older, were male, had a family history of AMD, and had a shorter axial length were at an increased risk for AMD compared with those without these risk factors. We observed a significantly lower predicted prevalence of AMD among Chinese Americans compared with Latinos, even after controlling for all relevant covariates, suggesting that additional genetic or lifestyle differences may play an important role in determining AMD risk.


Assuntos
Americanos Asiáticos , Degeneração Macular/etnologia , Vigilância da População/métodos , Medição de Risco , População Urbana , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Estudos Transversais , Feminino , Humanos , Degeneração Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fotografação , Prevalência , Retina/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco
12.
Hum Hered ; 83(3): 130-152, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30669148

RESUMO

OBJECTIVES: There is evidence to suggest that asthma pathogenesis is affected by both genetic and epigenetic variation independently, and there is some evidence to suggest that genetic-epigenetic interactions affect risk of asthma. However, little research has been done to identify such interactions on a genome-wide scale. The aim of this studies was to identify genes with genetic-epigenetic interactions associated with asthma. METHODS: Using asthma case-control data, we applied a novel nonparametric gene-centric approach to test for interactions between multiple SNPs and CpG sites simultaneously in the vicinities of 18,178 genes across the genome. RESULTS: Twelve genes, PF4, ATF3, TPRA1, HOPX, SCARNA18, STC1, OR10K1, UPK1B, LOC101928523, LHX6, CHMP4B, and LANCL1, exhibited statistically significant SNP-CpG interactions (false discovery rate = 0.05). Of these, three have previously been implicated in asthma risk (PF4, ATF3, and TPRA1). Follow-up analysis revealed statistically significant pairwise SNP-CpG interactions for several of these genes, including SCARNA18, LHX6, and LOC101928523 (p = 1.33E-04, 8.21E-04, 1.11E-03, respectively). CONCLUSIONS: Joint effects of genetic and epigenetic variation may play an important role in asthma pathogenesis. Statistical methods that simultaneously account for multiple variations across chromosomal regions may be needed to detect these types of effects on a genome-wide scale.


Assuntos
Asma/genética , Epigênese Genética , Epistasia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Criança , Pré-Escolar , Simulação por Computador , Ilhas de CpG/genética , Metilação de DNA/genética , Feminino , Genoma Humano , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
13.
Int J Chron Obstruct Pulmon Dis ; 12: 3171-3181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29133979

RESUMO

Background: COPD is the third leading cause of death in the United States. Cigarette smoking accelerates the age-related forced expiratory volume in 1 s (FEV1) decline, an important determinant for the genesis of COPD. Hispanic smokers have lower COPD prevalence and FEV1 decline than non-Hispanic whites (NHWs). Patients and methods: A nutritional epidemiological study was conducted in the Lovelace Smokers cohort (LSC; n=1,829) and the Veterans Smokers cohort (n=508) to identify dietary nutrients (n=139) associated with average FEV1 and its decline and to assess whether nutrient intakes could explain ethnic disparity in FEV1 decline between Hispanics and NHW smokers. Results: Nutrients discovered and replicated to be significantly associated with better average FEV1 included magnesium, folate, niacin, vitamins A and D, eicosenoic fatty acid (20:1n9), eicosapentaenoic acid (20:5n3), docosapentaenoic acid (DPA; 22:5n3), docosahexaenoic acid (22:6n3), and fiber. In addition, greater intakes of eicosenoic fatty acid and DPA were associated with slower FEV1 decline in the LSC. Among omega 3 polyunsaturated fatty acids, DPA is the most potent nutrient associated with better average FEV1 and slower FEV1 decline. Adverse effect of continuous current smoking on FEV1 decline was completely negated in LSC members with high DPA intake (>20 mg/day). Slower FEV1 decline in Hispanics compared to NHWs may be due to the greater protection of eicosenoic fatty acid and DPA for FEV1 decline rather than greater intake of protective nutrients in this ethnic group. Conclusion: The protective nutrients for the preservation of FEV1 in ever smokers could lay foundation for designing individualized nutritional intervention targeting "optimal physiological levels" in human to improve lung function in ever smokers. Ethnic disparity in FEV1 decline may be explained by difference in magnitude of protection of dietary intakes of eicosenoic fatty acid and DPA between Hispanics and NHWs.


Assuntos
Fumar Cigarros/fisiopatologia , Dieta/etnologia , Ácido Eicosapentaenoico/administração & dosagem , Grupo com Ancestrais do Continente Europeu , Ácidos Graxos Insaturados/administração & dosagem , Hispano-Americanos , Pulmão/fisiopatologia , Estado Nutricional/etnologia , Fumantes , Adulto , Idoso , Fumar Cigarros/efeitos adversos , Fumar Cigarros/etnologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Disparidades nos Níveis de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , New Mexico/epidemiologia , Prevalência , Fatores de Proteção , Fatores de Risco
14.
Am J Epidemiol ; 186(7): 778-786, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978190

RESUMO

Genetic and environmental factors are both known to contribute to susceptibility to complex diseases. Therefore, the study of gene-environment interaction (G×E) has been a focus of research for several years. In this article, select examples of G×E from the literature are described to highlight different approaches and underlying principles related to the success of these studies. These examples can be broadly categorized as studies of single metabolism genes, genes in complex metabolism pathways, ranges of exposure levels, functional approaches and model systems, and pharmacogenomics. Some studies illustrated the success of studying exposure metabolism for which candidate genes can be identified. Moreover, some G×E successes depended on the availability of high-quality exposure assessment and longitudinal measures, study populations with a wide range of exposure levels, and the inclusion of ethnically and geographically diverse populations. In several examples, large population sizes were required to detect G×Es. Other examples illustrated the impact of accurately defining scale of the interactions (i.e., additive or multiplicative). Last, model systems and functional approaches provided insights into G×E in several examples. Future studies may benefit from these lessons learned.


Assuntos
Doença/etiologia , Interação Gene-Ambiente , Pesquisa Biomédica , Doença/genética , Exposição Ambiental , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Biológicos
15.
Am J Epidemiol ; 186(7): 762-770, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978192

RESUMO

The analysis of gene-environment interaction (G×E) may hold the key for further understanding the etiology of many complex traits. The current availability of high-volume genetic data, the wide range in types of environmental data that can be measured, and the formation of consortiums of multiple studies provide new opportunities to identify G×E but also new analytical challenges. In this article, we summarize several statistical approaches that can be used to test for G×E in a genome-wide association study. These include traditional models of G×E in a case-control or quantitative trait study as well as alternative approaches that can provide substantially greater power. The latest methods for analyzing G×E with gene sets and with data in a consortium setting are summarized, as are issues that arise due to the complexity of environmental data. We provide some speculation on why detecting G×E in a genome-wide association study has thus far been difficult. We conclude with a description of software programs that can be used to implement most of the methods described in the paper.


Assuntos
Doença/etiologia , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Modelos Estatísticos , Software , Teorema de Bayes , Doença/genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Análise de Sequência de DNA
16.
Am J Epidemiol ; 186(7): 753-761, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978193

RESUMO

Recently, many new approaches, study designs, and statistical and analytical methods have emerged for studying gene-environment interactions (G×Es) in large-scale studies of human populations. There are opportunities in this field, particularly with respect to the incorporation of -omics and next-generation sequencing data and continual improvement in measures of environmental exposures implicated in complex disease outcomes. In a workshop called "Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases," held October 17-18, 2014, by the National Institute of Environmental Health Sciences and the National Cancer Institute in conjunction with the annual American Society of Human Genetics meeting, participants explored new approaches and tools that have been developed in recent years for G×E discovery. This paper highlights current and critical issues and themes in G×E research that need additional consideration, including the improved data analytical methods, environmental exposure assessment, and incorporation of functional data and annotations.


Assuntos
Doença/etiologia , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Doença/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Software
17.
Circ Cardiovasc Genet ; 10(3)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28620071

RESUMO

BACKGROUND: Several consortia have pursued genome-wide association studies for identifying novel genetic loci for blood pressure, lipids, hypertension, etc. They demonstrated the power of collaborative research through meta-analysis of study-specific results. METHODS AND RESULTS: The Gene-Lifestyle Interactions Working Group was formed to facilitate the first large, concerted, multiancestry study to systematically evaluate gene-lifestyle interactions. In stage 1, genome-wide interaction analysis is performed in 53 cohorts with a total of 149 684 individuals from multiple ancestries. In stage 2 involving an additional 71 cohorts with 460 791 individuals from multiple ancestries, focused analysis is performed for a subset of the most promising variants from stage 1. In all, the study involves up to 610 475 individuals. Current focus is on cardiovascular traits including blood pressure and lipids, and lifestyle factors including smoking, alcohol, education (as a surrogate for socioeconomic status), physical activity, psychosocial variables, and sleep. The total sample sizes vary among projects because of missing data. Large-scale gene-lifestyle or more generally gene-environment interaction (G×E) meta-analysis studies can be cumbersome and challenging. This article describes the design and some of the approaches pursued in the interaction projects. CONCLUSIONS: The Gene-Lifestyle Interactions Working Group provides an excellent framework for understanding the lifestyle context of genetic effects and to identify novel trait loci through analysis of interactions. An important and novel feature of our study is that the gene-lifestyle interaction (G×E) results may improve our knowledge about the underlying mechanisms for novel and already known trait loci.


Assuntos
Interação Gene-Ambiente , Estilo de Vida/etnologia , Pressão Sanguínea , Estudos de Coortes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lipídeos/sangue , Modelos Teóricos , Fenótipo , Polimorfismo de Nucleotídeo Único , Projetos de Pesquisa
18.
Int J Cancer ; 140(5): 1000-1008, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27778348

RESUMO

Incidence rates of childhood leukemia in the United States have steadily increased over the last several decades, but only recently have disparities in the increase in incidence been recognized. In the current analysis, Surveillance, Epidemiology and End Results (SEER) data were used to evaluate recent trends in the incidence of childhood leukemia diagnosed at age 0-19 years from 1992 to 2013, overall and by age, race/ethnicity, gender and histologic subtype. Hispanic White children were more likely than non-Hispanic White, non-Hispanic Black or non-Hispanic Asian children to be diagnosed with acute lymphocytic leukemia (ALL) from 2009 to 2013. From 1992 to 2013, a significant increase in ALL incidence was observed for Hispanic White children [annual percent change (APC)Hispanic = 1.08, 95% CI: 0.59, 1.58]; no significant increase was observed for non-Hispanic White, Black or Asian children. ALL incidence increased by about 3% per year from 1992 to 2013 for Hispanic White children diagnosed from 15 to 19 years (APC = 2.67; 95% CI: 0.88, 4.49) and by 2% for those 10-14 years (APC = 2.09; 95% CI: 0.57, 3.63), while no significant increases in incidence were observed in non-Hispanic White, Black, or Asian children of the same age. Acute myeloid leukemia (AML) incidence increased among non-Hispanic White children under 1 year at diagnosis, and among Hispanic White children diagnosed at age 1-4. The increase in incidence rates of childhood ALL appears to be driven by rising rates in older Hispanic children (10-14, and 15-19 years). Future studies are needed to evaluate reasons for the increase in ALL among older Hispanic children.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Morbidade/tendências , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia , Adulto Jovem
19.
Am J Respir Crit Care Med ; 195(10): 1373-1383, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27901618

RESUMO

RATIONALE: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. OBJECTIVES: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. METHODS: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. MEASUREMENTS AND MAIN RESULTS: In the European cohorts, 186 SNPs had an interaction P < 1 × 10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10-4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ß-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. CONCLUSIONS: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.


Assuntos
Poluição do Ar/estatística & dados numéricos , Asma/epidemiologia , Interação Gene-Ambiente , Emissões de Veículos , Asma/genética , Criança , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , América do Norte/epidemiologia , Polimorfismo de Nucleotídeo Único
20.
Am J Respir Crit Care Med ; 195(2): 179-188, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27494826

RESUMO

RATIONALE: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. OBJECTIVES: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. METHODS: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). MEASUREMENTS AND MAIN RESULTS: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. CONCLUSIONS: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).


Assuntos
Asma/sangue , Perfilação da Expressão Gênica , Adulto , Asma/genética , Asma/metabolismo , Asma/terapia , Linfócitos T CD4-Positivos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Transcriptoma , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA