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1.
Bioinformatics ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33453114

RESUMO

MOTIVATION: While gene-environment (GxE) interactions contribute importantly to many different phenotypes, detecting such interactions requires well-powered studies and has proven difficult. To address this, we combine two approaches to improve GxE power: simultaneously evaluating multiple phenotypes and using a two-step analysis approach. Previous work shows that the power to identify a main genetic effect can be improved by simultaneously analyzing multiple related phenotypes. For a univariate phenotype, two-step methods produce higher power for detecting a GxE interaction compared to single step analysis. Therefore, we propose a two-step approach to test for an overall GxE effect for multiple phenotypes. RESULTS: Using simulations we demonstrate that, when more than one phenotype has GxE effect (i.e., GxE pleiotropy), our approach offers substantial gain in power (18%-43%) to detect an aggregate-level GxE effect for a multivariate phenotype compared to an analogous two-step method to identify GxE effect for a univariate phenotype. We applied the proposed approach to simultaneously analyze three lipids, LDL, HDL and Triglyceride with the frequency of alcohol consumption as environmental factor in the UK Biobank. The method identified two loci with an overall GxE effect on the vector of lipids, one of which was missed by the competing approaches. AVAILABILITY: We provide an R package MPGE implementing the proposed approach which is available from CRAN: https://cran.r-project.org/web/packages/MPGE/index.html.

2.
PLoS One ; 15(11): e0242364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237978

RESUMO

BACKGROUND: Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. OBJECTIVE: Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. METHODS: Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. RESULTS: Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. CONCLUSIONS: We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.

3.
J Adolesc Health ; 67(6): 763-768, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33071164

RESUMO

PURPOSE: The aim of the study was to determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in a university student population. METHODS: This was a cross-sectional survey study based on the World Health Organization population-based seroepidemiological investigational protocol for SARS-CoV-2 conducted between April 29, 2020, and May 8, 2020, examining SARS-CoV-2 antibody prevalence among 790 university students in Los Angeles, CA. Participants completed a questionnaire on potential risk factors before blood sampling. Samples were analyzed using the EUROIMMUN Anti-SARS-CoV-2 ELISA (IgG) for the qualitative detection of IgG class antibodies to SARS-CoV-2 in human serum or plasma. RESULTS: The estimated prevalence of SARS-CoV-2 antibody was 4.0% (3.0%, 5.1%). Factors associated with having a positive test included history of anosmia and/or loss of taste (95% CI: 1.4-9.6). A history of respiratory symptoms, with or without fever, was not associated with a positive antibody test. CONCLUSIONS: Prevalence of SARS-CoV-2 antibodies in the undergraduate and graduate student university population was similar to community prevalence.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32966749

RESUMO

RATIONALE: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower LD in this region, which could facilitate identifying causal variants. OBJECTIVE: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals. METHODS AND MEASUREMENTS: We evaluated African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) (n=1,940), the Study of African Americans, Asthma, Genes & Environment (SAGE II) (n=885), and Study of the Genetic Causes of Complex Pediatric Disorders - Asthma (GCPD-A) (n=2,805). Associations with asthma onset at age <5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression quantitative trait locus (eQTL) analysis and phenome-wide association study (PheWAS) were performed on the lead variant. MAIN RESULTS: The meta-analyzed results from SAPPHIRE, SAGE II, and GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the eQTL analysis, rs11078928 was related to alternative splicing of gasdermin-B (GSDMB) transcripts. The PheWAS of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms. CONCLUSIONS: A splice acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.

5.
Cancer Med ; 9(10): 3563-3573, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32207560

RESUMO

BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ). CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

6.
J Neurooncol ; 147(2): 309-315, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32056145

RESUMO

INTRODUCTION: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

7.
Am J Respir Crit Care Med ; 201(4): 438-444, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31644884

RESUMO

Rationale: Although elevated air pollution exposure impairs lung-function development in childhood, it remains a challenge to use this information to estimate the potential public health benefits of air pollution interventions in exposed populations.Objectives: Apply G-computation to estimate hypothetical effects of several realistic scenarios for future air pollution reductions on lung growth.Methods: Mixed-effects linear regression was used to estimate FEV1 and FVC from age 11 to 15 years in 2,120 adolescents across 3 cohorts (1993-2001, 1997-2004, and 2007-2011). Models included regional pollutants (nitrogen dioxide [NO2] or particulate matter with an aerodynamic diameter ≤2.5 µm [PM2.5]) and other important covariates. Using G-computation, a causal inference-based method, we then estimated changes in mean lung growth in our population for hypothetical interventions on either NO2 or PM2.5. Confidence intervals (CIs) were computed by bootstrapping (N = 1,000).Measurements and Main Results: Compared with the effects of exposure from observed NO2 concentrations during the study period, had communities remained at 1994 to 1997 NO2 levels, FEV1 and FVC growth were estimated to have been reduced by 2.7% (95% CI, -3.6 to -1.8) and 4.2% (95% CI, -5.2 to -3.4), respectively. If NO2 concentrations had been reduced by 30%, we estimated a 4.4% increase in FEV1 growth (95% CI, 2.8-5.9) and a 7.1% increase in FVC growth (95% CI, 5.7-8.6). Comparable results were observed for PM2.5 interventions.Conclusions: We estimated that substantial increases in lung function would occur as a result of interventions that reduce NO2 or PM2.5 concentrations. These findings provide a quantification of potential health benefits of air quality improvement.


Assuntos
Poluição do Ar/efeitos adversos , Poluição do Ar/legislação & jurisprudência , Poluição do Ar/prevenção & controle , Exposição Ambiental/efeitos adversos , Exposição Ambiental/legislação & jurisprudência , Exposição Ambiental/prevenção & controle , Pulmão/crescimento & desenvolvimento , Adolescente , Poluição do Ar/estatística & dados numéricos , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Exposição Ambiental/estatística & dados numéricos , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino
8.
Neurooncol Adv ; 1(1): vdz031, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807733

RESUMO

Background: Epidemiological studies of adult glioma have identified genetic and environmental risk factors, but much remains unclear. The aim of the current study was to evaluate anthropometric, disease-related, and prediagnostic immune-related factors for relationship with glioma risk. Methods: We conducted a nested case-control study among the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. One hundred and twenty-four glioma cases were identified and each matched to four controls. Baseline characteristics were collected at enrollment and were evaluated for association with glioma status. Serum specimens were collected at yearly intervals and were analyzed for immune-related factors including TGF-ß1, TNF-α, total IgE, and allergen-specific IgE. Immune factors were evaluated at baseline in a multivariate conditional logistic regression model, along with one additional model that incorporated the latest available measurement. Results: A family history of glioma among first-degree relatives was associated with increased glioma risk (OR = 4.41, P = .002). In multivariate modeling of immune factors at baseline, increased respiratory allergen-specific IgE was inversely associated with glioma risk (OR for allergen-specific IgE > 0.35 PAU/L: 0.59, P = .03). A logistic regression model that incorporated the latest available measurements found a similar association for allergen-specific IgE (P = .005) and showed that elevated TGF-ß1 was associated with increased glioma risk (P-value for trend <.0001). Conclusion: The results from this prospective prediagnostic study suggest that several immune-related factors are associated with glioma risk. The association observed for TGF-ß1 when sampling closer to the time of diagnosis may reflect the nascent brain tumor's feedback on immune function.

9.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1177-1186, 2019 07.
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.


Assuntos
Ritmo Circadiano/fisiologia , Melatonina/metabolismo , Enfermeiras e Enfermeiros/normas , Jornada de Trabalho em Turnos/psicologia , Adulto , Feminino , Humanos , Masculino , Fatores de Risco
10.
Am J Epidemiol ; 188(4): 760-767, 2019 04 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.


Assuntos
Interação Gene-Ambiente , Modelos Genéticos , Asma/genética , Teorema de Bayes , Estudos de Casos e Controles , Criança , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/análise , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Software
11.
J Allergy Clin Immunol ; 143(3): 957-969, 2019 03.
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.


Assuntos
Asma/genética , Cromossomos Humanos Par 18 , Predisposição Genética para Doença , Hispano-Americanos/genética , Proteína Smad2/genética , Mapeamento Cromossômico , Humanos , Polimorfismo de Nucleotídeo Único
12.
Obesity (Silver Spring) ; 26(12): 1938-1948, 2018 12.
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.


Assuntos
Asma/genética , Expressão Gênica/genética , Obesidade/genética , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Adulto Jovem
14.
Nat Genet ; 50(8): 1072-1080, 2018 08.
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.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Antígenos HLA/genética , Rinite Alérgica/genética , Alérgenos/genética , Estudos de Casos e Controles , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Risco
15.
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.

17.
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
18.
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
19.
Am J Epidemiol ; 187(1): 45-52, 2018 01 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.


Assuntos
Poluentes Atmosféricos/toxicidade , Asma/epidemiologia , Exposição Ambiental/efeitos adversos , Hispano-Americanos/estatística & dados numéricos , Emissões de Veículos/toxicidade , Adolescente , Asma/etiologia , California/epidemiologia , Criança , Feminino , Humanos , Índios Norte-Americanos/estatística & dados numéricos , Estudos Longitudinais , Masculino , Estudos Prospectivos
20.
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.


Assuntos
Biomarcadores Tumorais/genética , Epigênese Genética , Grupos Étnicos/genética , Neoplasias Pulmonares/genética , Nutrientes/administração & dosagem , Fumar/etnologia , Escarro/metabolismo , Adulto , Idoso , Metilação de DNA , Dieta , Ingestão de Energia , Feminino , Seguimentos , Inativação Gênica , Humanos , Estudos Longitudinais , Neoplasias Pulmonares/dietoterapia , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , New Mexico , Estado Nutricional , Prognóstico , Regiões Promotoras Genéticas , Fumar/genética
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