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1.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

2.
Diabetes ; 68(5): 1073-1083, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936141

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

3.
Am J Hum Genet ; 104(2): 260-274, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639324

RESUMO

With advances in whole-genome sequencing (WGS) technology, more advanced statistical methods for testing genetic association with rare variants are being developed. Methods in which variants are grouped for analysis are also known as variant-set, gene-based, and aggregate unit tests. The burden test and sequence kernel association test (SKAT) are two widely used variant-set tests, which were originally developed for samples of unrelated individuals and later have been extended to family data with known pedigree structures. However, computationally efficient and powerful variant-set tests are needed to make analyses tractable in large-scale WGS studies with complex study samples. In this paper, we propose the variant-set mixed model association tests (SMMAT) for continuous and binary traits using the generalized linear mixed model framework. These tests can be applied to large-scale WGS studies involving samples with population structure and relatedness, such as in the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. SMMATs share the same null model for different variant sets, and a virtue of this null model, which includes covariates only, is that it needs to be fit only once for all tests in each genome-wide analysis. Simulation studies show that all the proposed SMMATs correctly control type I error rates for both continuous and binary traits in the presence of population structure and relatedness. We also illustrate our tests in a real data example of analysis of plasma fibrinogen levels in the TOPMed program (n = 23,763), using the Analysis Commons, a cloud-based computing platform.

4.
Genet Epidemiol ; 42(4): 320-332, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29601641

RESUMO

Many gene mapping studies of complex traits have identified genes or variants that influence multiple phenotypes. With the advent of next-generation sequencing technology, there has been substantial interest in identifying rare variants in genes that possess cross-phenotype effects. In the presence of such effects, modeling both the phenotypes and rare variants collectively using multivariate models can achieve higher statistical power compared to univariate methods that either model each phenotype separately or perform separate tests for each variant. Several studies collect phenotypic data over time and using such longitudinal data can further increase the power to detect genetic associations. Although rare-variant approaches exist for testing cross-phenotype effects at a single time point, there is no analogous method for performing such analyses using longitudinal outcomes. In order to fill this important gap, we propose an extension of Gene Association with Multiple Traits (GAMuT) test, a method for cross-phenotype analysis of rare variants using a framework based on the distance covariance. The approach allows for both binary and continuous phenotypes and can also adjust for covariates. Our simple adjustment to the GAMuT test allows it to handle longitudinal data and to gain power by exploiting temporal correlation. The approach is computationally efficient and applicable on a genome-wide scale due to the use of a closed-form test whose significance can be evaluated analytically. We use simulated data to demonstrate that our method has favorable power over competing approaches and also apply our approach to exome chip data from the Genetic Epidemiology Network of Arteriopathy.


Assuntos
Variação Genética , Característica Quantitativa Herdável , Simulação por Computador , Bases de Dados Genéticas , Exoma , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Modelos Genéticos , Fenótipo
5.
J Gerontol A Biol Sci Med Sci ; 73(4): 492-498, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28958070

RESUMO

Background: Adiposity depots may differentially affect cognition. African Americans (AA) have higher rates of obesity and dementia but lower visceral adipose tissue (VAT) than whites, yet are underrepresented in studies of adiposity and cognition. Our study compared relations of cognitive function to clinical adiposity measures and computed tomography (CT)-imaged abdominal adiposity in AA. Methods: CT-imaged subcutaneous adipose tissue (SAT) and VAT measurements were obtained in the AA cohort of the Genetic Epidemiology Network of Arteriopathy Study (N = 652, mean age 68 ± 8.4 years, 74% females, 59% obese, 82% hypertensive). Clinical adiposity measures included waist circumference (WC) and body mass index (BMI). Global cognition was operationalized as a global cognitive z-score generated from the average of four cognitive domain z-scores. Generalized estimating equations were used to examine cross-sectional associations between individual standardized adiposity measures and cognition, accounting for age, sex, education, smoking status, and familial clustering. A collective model was constructed including multiple supported adiposity measures and age-by-adiposity interactions. Results: In the collective model, higher WC was associated with worse global cognition, ß = -0.12 (95%CI: -0.21, -0.03); higher SAT was associated with better cognition, ß = 0.09 (0.01, 0.18); higher BMI was associated with worse cognition at younger ages with attenuation at older ages (BMI-by-age-interaction p = .004). VAT was not significantly associated with global cognition, ß = -0.03 (-0.07, 0.02). Conclusions: WC may be the simplest and most efficient measure of adiposity to assess with respect to cognition in clinical settings, although studies to determine mechanistic effects of subcutaneous and other adiposity depots on cognition are warranted.

6.
Am J Epidemiol ; 186(10): 1149-1158, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29149250

RESUMO

The association between cigarette smoking and inflammation is well known. However, the biological mechanisms behind the association are not fully understood, particularly the role of DNA methylation, which is known to be affected by smoking. Using 2-step epigenetic Mendelian randomization, we investigated the role of DNA methylation in the association between cigarette smoking and inflammation. In 822 African Americans from the Genetic Epidemiology Network of Arteriopathy, phase 2 (Jackson, Mississippi; 2000-2005), study population, we examined the association of cigarette smoking with DNA methylation using single nucleotide polymorphisms identified in previous genome-wide association studies of cigarette smoking. We then investigated the association of DNA methylation with levels of inflammatory markers using cis-methylation quantitative trait loci single nucleotide polymorphisms. We found that current smoking status was associated with the DNA methylation levels (M values) of cg03636183 in the coagulation factor II (thrombin) receptor-like 3 gene (F2RL3) (M = -0.64, 95% confidence interval (CI): -0.84, -0.45) and of cg19859270 in the G protein-coupled receptor 15 gene (GPR15) (M = -0.21, 95% CI: -0.27, -0.15). The DNA methylation levels of cg03636183 in F2RL3 were associated with interleukin-18 concentration (-0.11 pg/mL, 95% CI: -0.19, -0.04). These combined negative effects suggest that cigarette smoking increases interleukin-18 levels through the decrease in DNA methylation levels of cg03636183 in F2RL3.


Assuntos
Afro-Americanos/genética , Fumar Cigarros/efeitos adversos , Metilação de DNA/genética , Epigênese Genética , Inflamação/genética , Análise da Randomização Mendeliana , Idoso , Biomarcadores/sangue , Fumar Cigarros/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamação/etiologia , Masculino , Mississippi , Polimorfismo de Nucleotídeo Único
7.
Nat Genet ; 49(1): 125-130, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27918534

RESUMO

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.


Assuntos
Adipócitos/citologia , Distribuição da Gordura Corporal , Diferenciação Celular , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Adipócitos/metabolismo , Animais , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenótipo
8.
Curr Atheroscler Rep ; 18(11): 67, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27726072

RESUMO

PURPOSE OF REVIEW: This review provides a brief synopsis of sexual dimorphism in atherosclerosis with an emphasis on genetic studies aimed to better understand the atherosclerotic process and clinical outcomes in women. Such studies are warranted because development of atherosclerosis, impact of several traditional risk factors, and burden of coronary heart disease (CHD) differ between women and men. RECENT FINDINGS: While most candidate gene studies pool women and men and adjust for sex, some sex-specific studies provide evidence of association between candidate genes and prevalent and incident CHD in women. So far, most genome-wide association studies (GWAS) also failed to consider sex-specific associations. The few GWAS focused on women tended to have small sample sizes and insufficient power to reject the null hypothesis of no association even if associations exist. Few studies consider that sex can modify the effect of gene variants on CHD. Sufficiently large-scale genetic studies in women of different race/ethnic groups, taking into account possible gene-gene and gene-environment interactions as well as hormone-mediated epigenetic mechanisms, are needed. Using the same disease definition for women and men might not be appropriate. Accurate phenotyping and inclusion of relevant outcomes in women, together with targeting the entire spectrum of atherosclerosis, could help address the contribution of genes to sexual dimorphism in atherosclerosis. Discovered genetic loci should be taken forward for replication and functional studies to elucidate the plausible underlying biological mechanisms. A better understanding of the etiology of atherosclerosis in women would facilitate future prevention efforts and interventions.


Assuntos
Doenças Cardiovasculares/genética , Doenças Cardiovasculares/epidemiologia , Feminino , Pesquisa em Genética , Estudo de Associação Genômica Ampla , Humanos , Prevalência , Fatores de Risco , Caracteres Sexuais
9.
Am J Hum Genet ; 98(3): 525-540, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26942286

RESUMO

Increasing empirical evidence suggests that many genetic variants influence multiple distinct phenotypes. When cross-phenotype effects exist, multivariate association methods that consider pleiotropy are often more powerful than univariate methods that model each phenotype separately. Although several statistical approaches exist for testing cross-phenotype effects for common variants, there is a lack of similar tests for gene-based analysis of rare variants. In order to fill this important gap, we introduce a statistical method for cross-phenotype analysis of rare variants using a nonparametric distance-covariance approach that compares similarity in multivariate phenotypes to similarity in rare-variant genotypes across a gene. The approach can accommodate both binary and continuous phenotypes and further can adjust for covariates. Our approach yields a closed-form test whose significance can be evaluated analytically, thereby improving computational efficiency and permitting application on a genome-wide scale. We use simulated data to demonstrate that our method, which we refer to as the Gene Association with Multiple Traits (GAMuT) test, provides increased power over competing approaches. We also illustrate our approach using exome-chip data from the Genetic Epidemiology Network of Arteriopathy.


Assuntos
Variação Genética , Modelos Genéticos , Fenótipo , Pressão Sanguínea , Índice de Massa Corporal , Sistema Cardiovascular/metabolismo , HDL-Colesterol/sangue , Bases de Dados Genéticas , Exoma , Estudos de Associação Genética , Genoma Humano , Genótipo , Humanos , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos
10.
Diabetes Metab Res Rev ; 32(6): 565-71, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26663816

RESUMO

BACKGROUND: Substantial evidence supports an association between diabetes and arsenic at high exposure levels, but results are mixed at low exposure levels. The aetiology of diabetes involves insulin resistance and ß-cell dysfunction. However, only a few epidemiologic studies have examined measures of insulin resistance and ß-cell function in relation to arsenic exposure, and no studies have tested for associations with the oral glucose tolerance test (OGTT). We examined the association between urinary total arsenic and OGTT-based markers of insulin sensitivity and ß-cell function. METHODS: We studied 221 non-diabetic adults (mean age = 52.5 years) from the Amish Family Diabetes Study. We computed OGTT-based validated measures of insulin sensitivity and ß-cell function. Generalized estimating equations accounting for sibship were used to estimate associations. RESULTS: After adjusting for age, sex, waist-to-hip ratio and urinary creatinine, an interquartile range increase in urinary total arsenic (6.24 µg/L) was significantly, inversely associated with two insulin sensitivity measures (Stumvoll metabolic clearance rate = -0.23 mg/(kg min), (95% CI: -0.38, -0.089), p = 0.0015; Stumvoll insulin sensitivity index = -0.0029 µmol/(kg min pM), (95% CI: -0.0047, -0.0011), p = 0.0015). Urinary total arsenic was also significantly associated with higher fasting glucose levels (0.57 mg/dL (95% CI: 0.06, 1.09) per interquartile range increase, p = 0.029). No significant associations were found between urinary total arsenic and ß-cell function measures. CONCLUSIONS: This preliminary study found that urinary total arsenic was associated with insulin sensitivity but not ß-cell function measures, suggesting that low-level arsenic exposure may influence diabetes risk through impairing insulin sensitivity. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Arsênico/efeitos adversos , Arsênico/urina , Diabetes Mellitus/induzido quimicamente , Exposição Ambiental/efeitos adversos , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Adulto , Amish/estatística & dados numéricos , Biomarcadores/urina , Feminino , Seguimentos , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
11.
Metabolism ; 64(9): 1013-21, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26026367

RESUMO

OBJECTIVE: The relationship between glycemic control and adverse outcomes found in a population with diabetes has seldom been evaluated in patients with type 2 diabetes. We explored the association between hemoglobin A1c (HbA1c) and hospitalization risks within one-year and eight-year follow-up periods. METHODS: We conducted a retrospective cohort study on 57,061 patients with type 2 diabetes from National Diabetes Case Management Program during 2002-2004 in Taiwan. HbA1c at baseline and in-hospital mortality, all-cause and cause-specific hospitalization over one year and eight years were analyzed. RESULTS: After multivariate adjustment, one-year risk was higher for cases with HbA1c level <6%, 9-10%, ≥10% versus 6-7% for all-cause hospitalization (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.03-1.20; 1.08, 1.01-1.16, and 1.19, 1.12-1.26, respectively) and for ≥10% for diabetes-related hospitalization (1.68, 1.46-1.92). Yet each 1-step increment in HbA1c category (<6.0, 6.0-6.9, 7.0-7.9, 8.0-8.9, 9.0-9.9 and ≥10.0%) showed linkage with lower risk of hypoglycemia hospitalization (0.81, 95% CI: 0.74-0.88). For eight-year risk, subjects with HbA1c level <6%, and ≥10% were more likely to have in-hospitality mortality (1.16, 1.03-1.31, and 1.23, 1.11-1.35, respectively). Each 1-step increment in HbA1c category showed an association with higher risks of all-cause and diabetes-related hospitalization (1.04, 1.03-1.05, and 1.15, 1.14-1.17, respectively). CONCLUSIONS: Higher HbA1c level correlated with lower one-year risk due to hypoglycemia hospitalization but increased one-year and eight-year risks due to all-cause and diabetes-specific hospitalization among Chinese people with type 2 diabetes in Taiwan. Future study must ascertain how to meet HbA1c targets and improve outcome without risk to this population.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Hipoglicemia/tratamento farmacológico , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/metabolismo , Mortalidade Hospitalar , Humanos , Hipoglicemia/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Taiwan/epidemiologia , Resultado do Tratamento
12.
BMC Med Genomics ; 8: 21, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25958224

RESUMO

BACKGROUND: Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression. METHODS: We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study. RESULTS: We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved. CONCLUSION: These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.


Assuntos
Cromossomos Humanos Par 9/ultraestrutura , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Idoso , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , RNA Mensageiro/metabolismo , Análise de Sequência de DNA
13.
Circ Cardiovasc Genet ; 8(3): 507-15, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25805414

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2D) and cardiovascular disease share risk factors and subclinical atherosclerosis (SCA) predicts events in those with and without diabetes mellitus. T2D genetic risk may predict both T2D and SCA. We hypothesized that greater T2D genetic risk is associated with higher extent of SCA. METHODS AND RESULTS: In a cross-sectional analysis, including ≤9210 European Americans, 3773 African Americans, 1446 Hispanic Americans, and 773 Chinese Americans without known cardiovascular disease and enrolled in the Framingham Heart Study, Coronary Artery Risk Development in Young Adults, Multi-Ethnic Study of Atherosclerosis, and Genetic Epidemiology Network of Arteriopathy studies, we tested a 62 T2D-loci genetic risk score for association with measures of SCA, including coronary artery or abdominal aortic calcium score, common and internal carotid artery intima-media thickness, and ankle-brachial index. We used ancestry-stratified linear regression models, with random effects accounting for family relatedness when appropriate, applying a genetic-only (adjusted for sex) and a full SCA risk factors-adjusted model (significance, P<0.01=0.05/5, number of traits analyzed). An inverse association with coronary artery calcium score in Multi-Ethnic Study of Atherosclerosis Europeans (fully-adjusted P=0.004) and with common carotid artery intima-media thickness in the Framingham Heart Study (P=0.009) was not confirmed in other study cohorts, either separately or in meta-analysis. Secondary analyses showed no consistent associations with ß-cell and insulin resistance genetic risk sub-scores in the Framingham Heart Study and in the Coronary Artery Risk Development in Young Adults. CONCLUSIONS: SCA does not have a major genetic component linked to a burden of 62 T2D loci identified by large genome-wide association studies. A shared T2D-SCA genetic basis, if any, might become apparent from better functional information about both T2D and cardiovascular disease risk loci.


Assuntos
Aterosclerose/genética , Diabetes Mellitus Tipo 2/genética , Grupos Étnicos/genética , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/patologia , Biomarcadores/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Am J Hum Genet ; 96(4): 543-54, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25799106

RESUMO

Sequencing and exome-chip technologies have motivated development of novel statistical tests to identify rare genetic variation that influences complex diseases. Although many rare-variant association tests exist for case-control or cross-sectional studies, far fewer methods exist for testing association in families. This is unfortunate, because cosegregation of rare variation and disease status in families can amplify association signals for rare variants. Many researchers have begun sequencing (or genotyping via exome chips) familial samples that were either recently collected or previously collected for linkage studies. Because many linkage studies of complex diseases sampled affected sibships, we propose a strategy for association testing of rare variants for use in this study design. The logic behind our approach is that rare susceptibility variants should be found more often on regions shared identical by descent by affected sibling pairs than on regions not shared identical by descent. We propose both burden and variance-component tests of rare variation that are applicable to affected sibships of arbitrary size and that do not require genotype information from unaffected siblings or independent controls. Our approaches are robust to population stratification and produce analytic p values, thereby enabling our approach to scale easily to genome-wide studies of rare variation. We illustrate our methods by using simulated data and exome chip data from sibships ascertained for hypertension collected as part of the Genetic Epidemiology Network of Arteriopathy (GENOA) study.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética/genética , Modelos Estatísticos , Taxa de Mutação , Doenças Raras/genética , Irmãos , Afro-Americanos/genética , Simulação por Computador , Humanos , Hipertensão/genética
15.
J Am Geriatr Soc ; 62(12): 2303-10, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25516026

RESUMO

OBJECTIVES: To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. DESIGN: Cross-sectional analysis using generalized estimating equations to account for familial clustering; standardized ß-coefficients, adjusted for age, sex, and education are reported. SETTING: Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. PARTICIPANTS: Genetic Epidemiology Network of Arteriopathy (GENOA)-Genetics of Microangiopathic Brain Injury (GMBI) Study participants. MEASUREMENTS: Associations between inflammation (high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26-95, 64% women, 52% AA, 75% with hypertension). RESULTS: In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: -0.11, P = .009; processing speed: -0.11, P < .001; language: -0.08, P = .002; memory: -0.09, P = .008; executive function: -0.07, P = .03); sTNFR1 was associated with slower processing speed (-0.08, P < .001) and poorer executive function (-0.08, P = .008); higher CRP was associated with slower processing speed (-0.04, P = .024), and higher IL6 was associated with poorer executive function (-0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (-0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. CONCLUSION: In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFα activity.


Assuntos
Afro-Americanos , Biomarcadores/sangue , Transtornos Cognitivos/sangue , Transtornos Cognitivos/etnologia , Grupo com Ancestrais do Continente Europeu , Doenças Vasculares/sangue , Doenças Vasculares/etnologia , Proteína C-Reativa/metabolismo , Transtornos Cognitivos/epidemiologia , Feminino , Humanos , Inflamação/sangue , Inflamação/epidemiologia , Inflamação/etnologia , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Mississippi/epidemiologia , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Fatores de Risco , Doenças Vasculares/epidemiologia
16.
BMC Med Genet ; 15: 89, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25185447

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity. METHODS: As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study's Offspring Cohort (N = 1,140). RESULTS: We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455). CONCLUSIONS: Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.


Assuntos
Pressão Sanguínea/genética , Calcinose/genética , Cromossomos Humanos Par 9 , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Idoso , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
17.
Am J Hum Genet ; 95(1): 66-76, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24975946

RESUMO

Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy by using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques. RNA sequencing of peripheral blood from a discovery set of CAC cases and controls was used to identify dysregulated genes, which were validated by ClinSeq and Framingham Heart Study data. Only a single gene, TREML4, was upregulated in CAC cases in both studies. Further examination showed that rs2803496 was a TREML4 cis-eQTL and that the minor allele at this locus conferred up to a 6.5-fold increased relative risk of CAC. We characterized human TREML4 and demonstrated by immunohistochemical techniques that it is localized in macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease). Finally, we determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification. Our findings connect multimodal genomics data with a commonly used clinical marker of cardiovascular disease.


Assuntos
Calcinose , Vasos Coronários/patologia , DNA/metabolismo , Proteínas/metabolismo , RNA/metabolismo , Receptores Imunológicos/fisiologia , Sequência de Bases , Primers do DNA , Células HEK293 , Humanos , Locos de Características Quantitativas , Receptores Imunológicos/genética
18.
Atherosclerosis ; 235(2): 488-95, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24953488

RESUMO

BACKGROUND AND AIM: Previous studies reporting on estimates of heritability of cardiovascular risk factors in Chinese are limited. This study aims to estimate the heritability of cardiovascular risk factors in relatives of residents who participated in the Taichung Community Health Study (TCHS) and Family Cohort (TCHS-FC) while controlling as many potential confounders as possible. METHODS: A total of 1564 study subjects from 494 families with members aged 12-91 years were enrolled from a random sample of participants of TCHS and their family members (TCHS-FC) from 2009 to 2012. Anthropometric measurement, body composition, blood pressure, plasma lipids, fasting glucose, insulin, highly sensitive C-reactive protein (hs-CRP), brachial-ankle pulse wave velocity (baPWV), and the ankle-brachial index (ABI), as well as a questionnaire interview, were obtained from each participant. RESULTS: Cardiovascular risk factors with estimates of heritability greater than 30% after multivariate adjustment were triglyceride (h(2) = 0.41), HDL-C (h(2) = 0.49), LDL-C (h(2) = 0.47), total cholesterol (h(2) = 0.46), hip circumference (h(2) = 0.44), weight (h(2) = 0.42), insulin (h(2) = 0.39), hs-CRP (h(2) = 0.38), BMI (h(2) = 0.38), and percent body fat mass (h(2) = 0.35). Correlation coefficients for significant sibling varied from 0.10 for weight to 0.47 for LDL-C whereas those for significant parent-offspring varied from 0.09 for fasting plasma glucose to 0.43 for baPWV. CONCLUSIONS: This study demonstrated significant heritability and familial aggregation of cardiovascular risk factors in a random sample of ethnic Chinese population.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Saúde da Família , Adolescente , Adulto , Idoso , Índice Tornozelo-Braço , Grupo com Ancestrais do Continente Asiático , Criança , Estudos Transversais , Saúde da Família/etnologia , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Análise de Onda de Pulso , Fatores de Risco , Taiwan/epidemiologia
19.
Hereditary Genet ; 3(3)2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26807331

RESUMO

Age is a well-established risk factor for chronic diseases. However, the cellular and molecular changes associated with aging processes that are related to chronic disease initiation and progression are not well-understood. Thus, there is an increased need to identify new markers of cellular and molecular changes that occur during aging processes. In this study, we use genome-wide DNA methylation from 26,428 CpG sites in 13,877 genes to investigate the relationship between age and epigenetic variation in the peripheral blood cells of 972 African American adults from the Genetic Epidemiology Network of Arteriopathy (GENOA) study (mean age=66.3 years, range=39-95). Age was significantly associated with 7,601 (28.8%) CpG sites after Bonferroni correction for α=0.05 (p<1.89×10-6). Due to the extraordinarily strong associations between age and many of the CpG sites (>7,000 sites with p-values ranging from 10-6 to 10-43), we investigated how well the DNA methylation markers predict age. We found that 2,095 (7.9%) CpG sites were significant predictors of age after Bonferroni correction. The top five principal components of the 2,095 age-associated CpG sites accounted for 69.3% of the variability in these CpG sites, and they explained 26.8% of the variation in age. The associations between methylation markers and adult age are so ubiquitous and strong that we hypothesize that DNA methylation patterns may be an important measure of cellular aging processes. Given the highly correlated nature of the age-associated epigenome (as evidenced by the principal components analysis), whole pathways may be regulated as a consequence of aging.

20.
Hum Mol Genet ; 23(3): 782-95, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24057673

RESUMO

Genome-wide association studies (GWAS) have uncovered many genetic associations for cardiovascular disease (CVD). However, data are limited regarding causal genetic variants within implicated loci. We sought to identify regulatory variants (cis- and trans-eQTLs) affecting expression levels of 93 genes selected by their proximity to SNPs with significant associations in prior GWAS for CVD traits. Expression levels were measured by qRT-PCR in leukocytes from 1846 Framingham Heart Study participants. An additive genetic model was applied to 2.5 million imputed SNPs for each gene. Approximately 45% of genes (N = 38) harbored at least one cis-eSNP after a regional multiple-test adjustment. Applying a more rigorous significance threshold (P < 5 × 10(-8)), we found the expression level of 10 genes was significantly associated with more than one cis-eSNP. The top cis-eSNPs for 7 of these 10 genes exhibited moderate-to-strong association with ≥ 1 CVD clinical phenotypes. Several eSNPs or proxy SNPs (r(2) = 1) were replicated by other eQTL studies. After adjusting for the lead GWAS SNPs for the 10 genes, expression variances explained by top cis-eSNPs were attenuated markedly for LPL, FADS2 and C6orf184, suggesting a shared genetic basis for the GWAS and expression trait. A significant association between cis-eSNPs, gene expression and lipid levels was discovered for LPL and C6orf184. In conclusion, strong cis-acting variants are localized within nearly half of the GWAS loci studied, with particularly strong evidence for a regulatory role of the top GWAS SNP for expression of LPL, FADS2 and C6orf184.


Assuntos
Aterosclerose/genética , Doenças Cardiovasculares/genética , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Ácidos Graxos Dessaturases/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Leucócitos/fisiologia , Lipídeos/sangue , Lipídeos/genética , Lipase Lipoproteica/genética , Massachusetts , Modelos Genéticos , Pseudogenes/genética , Locos de Características Quantitativas , Reprodutibilidade dos Testes , Fatores de Risco
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