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Genetically Low Antioxidant Protection and Risk of Cardiovascular Disease and Heart Failure in Diabetic Subjects.

ABSTRACT: Hyperglycemia-induced oxidative stress is one mechanism believed to underlie diabetic vascular disease. We tested the hypothesis that diabetic subjects heterozygous for extracellular superoxide dismutase (SOD3) R213G, which entails lower antioxidant capacity in tissues, have increased risk of cardiovascular disease and heart failure.We used the prospective Copenhagen General Population Study and Copenhagen City Heart Study and genotyped 95,871 individuals for the rs1799895 R213G variation in the SOD3 gene, of which 4498 had diabetes. We used national hospitalization and death registers to assess cardiovascular disease and heart failure.Out of 95,871 individuals, we identified 93,521 R213G non-carriers (213RR, 97.5%), 2336 heterozygotes (213RG, 2.4%) and 14 homozygotes (213GG, 0.01%). In diabetic subjects, the hazard ratio for cardiovascular disease in R213G heterozygotes compared to non-carriers was 2.32 (95% CI 1·44-3.75), with a corresponding hazard ratio in non-diabetic subjects of 0.97 (0·80-1.19) (p for interaction 0.002). For heart failure, the hazard ratios in R213G heterozygotes compared to non-carriers were 2.19 (1.28-3.76) in diabetic and 0.68 (0.49-0.92) in non-diabetic subjects (p for interaction < 0.001).Risk of cardiovascular disease and heart failure was higher in R213G heterozygotes versus non-carriers in diabetic subjects, but not in non-diabetic subjects.

SUBMITTER: Kobylecki CJ

PROVIDER: S-EPMC4703764 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Genetically Low Antioxidant Protection and Risk of Cardiovascular Disease and Heart Failure in Diabetic Subjects.

Kobylecki Camilla J CJ Afzal Shoaib S Nordestgaard Børge G BG

EBioMedicine 20151114 12

<h4>Background</h4>Hyperglycemia-induced oxidative stress is one mechanism believed to underlie diabetic vascular disease. We tested the hypothesis that diabetic subjects heterozygous for extracellular superoxide dismutase (SOD3) R213G, which entails lower antioxidant capacity in tissues, have increased risk of cardiovascular disease and heart failure.<h4>Methods</h4>We used the prospective Copenhagen General Population Study and Copenhagen City Heart Study and genotyped 95,871 individuals for t ...[more]

PMID: 26844281

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Project description:Background: Positive associations between inflammatory biomarkers and the risk of heart failure (HF) have been reported in conventional observational studies. However, the causal effects of inflammatory biomarkers on HF have not been fully elucidated. We conducted a Mendelian randomization (MR) study to examine the possible etiological roles of inflammatory biomarkers in HF. Methods: Summary statistical data for the associations between single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP), fibrinogen, and components of the interleukin-1 (IL-1)-interleukin-6 (IL-6) inflammatory signaling pathway, namely, interleukin-1β (IL-1β), IL-1 receptor antagonist (IL-1ra), IL-6, and soluble IL-6 receptor (sIL-6r), were obtained from genome-wide association studies (GWASs) for individuals of European descent. The GWAS dataset of 977,323 participants of European ancestry, which included 47,309 HF cases and 930,014 controls, was collected to identify genetic variants underlying HF. A two-sample Mendelian randomization framework was implemented to examine the causality of the association between these inflammatory biomarkers and HF. Results: Our MR analyses found that genetically determined CRP and fibrinogen were not causally associated with HF risk (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.84-1.02, p = 0.15; OR = 0.94, 95% CI = 0.55-1.58, p = 0.80, respectively). These findings remained consistent using different Mendelian randomization methods and in sensitivity analyses. For the IL-1-IL-6 pathway, causal estimates for IL-6 (OR = 0.86, 95% CI 0.81-0.91, p < 0.001), but not for IL-1β, IL-1ra, or sIL-6r, were significant. However, the association between genetically determined IL-6 and HF risk became non-significant after excluding SNPs with potential pleiotropy (OR = 0.89, 95% CI = 0.77-1.03, p = 0.12). Conclusion: Our study did not identify convincing evidence to support that CRP and fibrinogen, together with their upstream IL-1-IL-6 signaling pathway, were causally associated with HF risk.

Project description:BackgroundThe cardiovascular risk models and subclinical atherosclerotic indicators are both recommended for cardiovascular risk stratification. The accordance between the incidence of subclinical atherosclerosis and subjects with low and moderate cardiovascular risk is unclear.HypothesisSubjects with low and moderate cardiovascular risk have a lower incidence of subclinical atherosclerosis compared with subjects with high risk.MethodsBrachial-ankle pulse wave velocity (BaPWV) and brachial flow-mediated dilation (BFMD) were measured in 421 subjects without a history of atherosclerotic cardiovascular disease (ASCVD) from October 2016 to January 2020. All subjects were classified into low, moderate, and high risk based on Framingham and China-par risk models respectively.ResultsMean age was 57.05 ± 9.35 years and 248 (58.9%) were male. In subjects with low, moderate, and high risk assessed by Framingham and China-par risk models, the percentage of abnormal BaPWV ( > 1400 cm/s) was 42.9%, 70.1%, 85.7%, and 40.4%, 71.4%, 89.7%, respectively. Meanwhile, the percentage of abnormal BFMD ( ≤ 7%) was 43.8%, 68.5%, 77.3%, and 44.9%,72.1%, and 76.6%. According to Framingham-based high-risk categories, positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity for BaPWV abnormality were 85.7%, 39.4%, 36.1%, and 87.5%, respectively. For BFMD abnormality, the values were 77.3%, 40.1%, 34.1%, and 81.8%, respectively. According to China-par high-risk categories, the values for BaPWV abnormality were 89.7%, 43.8%, 45.6%, and 89.0%, respectively. For BFMD abnormality, the values were 76.6%, 41.3%, 40.7%, and 77%, respectively. In multivariate analysis, age and blood pressure were the independent predictors for subclinical atherosclerosis in subjects with low-moderate risk.ConclusionsMore than one-half of subjects with low and moderate risk already have detectable subclinical atherosclerosis, indicating higher cardiovascular risk beyond the traditional stratification.

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Genetically Low Antioxidant Protection and Risk of Cardiovascular Disease and Heart Failure in Diabetic Subjects.

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Genetically Low Antioxidant Protection and Risk of Cardiovascular Disease and Heart Failure in Diabetic Subjects.

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