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Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.

ABSTRACT: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available.The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model.In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk.The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.

SUBMITTER: Zee RY

PROVIDER: S-EPMC3012433 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.

Zee Robert Y L RY Ridker Paul M PM Chasman Daniel I DI

Clinica chimica acta; international journal of clinical chemistry 20101016 1-2

<h4>Background</h4>Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available.<h4>Methods</h4>The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participan ...[more]

PMID: 20937264

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Project description:Aims: This study was aimed to apply a Mendelian randomization design to explore the causal association between coronavirus disease 2019 (COVID-19) and three cardio-cerebrovascular diseases, including atrial fibrillation, ischemic stroke, and coronary artery disease. Methods: Two-sample Mendelian randomization was used to determine the following: 1) the causal effect of COVID-19 on atrial fibrillation (55,114 case participants vs 482,295 control participants), coronary artery disease (34,541 case participants vs 261,984 control participants), and ischemic stroke (34,217 case participants vs 40,611 control participants), which were obtained from the European Bioinformatics Institute, and 2) the causal effect of three cardio-cerebrovascular diseases on COVID-19. The single-nucleotide polymorphisms (SNPs) of COVID-19 were selected from the summary-level genome-wide association study data of COVID-19-hg genome-wide association study (GWAS) meta-analyses (round 5) based on the COVID-19 Host Genetics Initiative for participants with European ancestry. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and Mendelian randomization (MR)-Egger approaches. Results: Genetically predicted hospitalized COVID-19 was suggestively associated with ischemic stroke, with an odds ratio (OR) of 1.049 [95% confidence interval (CI) 1.003-1.098; p = 0.037] in the COVID-19 Host Genetics Initiative GWAS. When excluding the UK Biobank (UKBB) data, our analysis revealed a similar odds ratio of 1.041 (95% CI 1.001-1.082; p = 0.044). Genetically predicted coronary artery disease was associated with critical COVID-19, with an OR of 0.860 (95% CI 0.760-0.973; p = 0.017) in the GWAS meta-analysis and an OR of 0.820 (95% CI 0.722-0.931; p = 0.002) when excluding the UKBB data, separately. Limited evidence of causal associations was observed between critical or hospitalized COVID-19 and other cardio-cerebrovascular diseases included in our study. Conclusion: Our findings provide suggestive evidence about the causal association between hospitalized COVID-19 and an increased risk of ischemic stroke. Besides, other factors potentially contribute to the risk of coronary artery disease in patients with COVID-19, but not genetics.

Project description:ImportanceSome prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps.ObjectiveTo investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women's Health Initiative (WHI).Design, setting, and participantsIn 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021.ExposuresAPOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery).Main outcomes and measuresAll confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods.ResultsOf 10 292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF.Conclusions and relevanceIn this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.

Project description:OBJECTIVE:Genetic risk factors for essential hypertension are largely unknown. The aim of the present study was to assess the association of 77 previously characterized gene variants in 52 candidate genes from various biological pathways with blood pressure (BP) progression and incident hypertension. METHODS:We analyzed data from 18 738 white women who participated in a prospective cohort study and were free of hypertension at baseline. BP progression at 48 months and incident hypertension during the entire follow-up according to the different genotypes were assessed by logistic regression and Cox proportional-hazards models, respectively. RESULTS:At 48 months of follow-up, 7889 of 16 635 women (47.4%) had BP progression. Only three of 70 polymorphisms with a minor allele frequency of at least 2% had a significant association with BP progression. The odds ratio [95% confidence interval (CI)] for 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (minor allele T), natriuretic peptide precursor A (NPPA) rs5063 (minor allele A) and NPPA rs5065 (minor allele C) were 1.05 (1.00-1.10), 0.84 (0.76-0.94) and 0.93 (0.88-1.00), respectively. After adjustment for multiple testing using the false discovery rate, only the NPPA rs5063 association remained significant. During a median follow-up of 9.8 years, 5540 of 18 738 women developed incident hypertension. Only five of 70 polymorphisms were significantly associated with incident hypertension. The hazard ratio (95% CI) for interleukin 6 (IL-6) rs1800795 (minor allele C), MTHFR rs1801133, NPPA rs5063, nitric oxide synthase 3 rs1799983 (minor allele T) and transforming growth factor, beta 1 rs1800469 (minor allele T) were 0.96 (0.92-1.00), 1.06 (1.02-1.10), 0.88 (0.80-0.96), 1.05 (1.01-1.09) and 1.05 (1.01-1.10), respectively. After adjustment for multiple testing, none of these associations remained significant. CONCLUSION:NPPA gene polymorphisms may have a role in BP progression and incident hypertension. Our data also provide moderate confirmatory evidence of association between MTHFR rs1801133 and the development of hypertension.

Dataset Information

Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.

Publications

Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.

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