Dataset Information

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

ABSTRACT:

Objective

The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study.

Research design and methods

Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia).

Results

CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE.

Conclusions

Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.

SUBMITTER: Bebu I

PROVIDER: S-EPMC8247524 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

Bebu Ionut I Keshavarzi Sareh S Gao Xiaoyu X Braffett Barbara H BH Canty Angelo J AJ Herman William H WH Orchard Trevor J TJ Dagogo-Jack Samuel S Nathan David M DM Lachin John M JM Paterson Andrew D AD

Diabetes care 20210421 6

<h4>Objective</h4>The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study.<h4>Research design and meth ...[more]

PMID: 33883194

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Project description:Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT, and 1 to 2 years post‐DCCT (EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F2α. Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F2α, an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P<0.003; −5.3% risk for 10% higher 2,3 dinor‐8 iso prostaglandin F2α, P=0.0092). In contrast, the oxidative markers myeloperoxidase and F2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00360815 and NCT00360893.

Project description:Background and objectivesIn trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes.Design, setting, participants, & measurementsWe studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously <30 mg/d), sustained microalbuminuria (AER, 30-299 mg/d on two consecutive visits), macroalbuminuria (AER≥300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER<30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (<60 ml/min per 1.73 m2 on two consecutive visits), and subclinical cardiovascular disease.ResultsAt least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification.ConclusionsIn type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes.

Dataset Information

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

Objective

Research design and methods

Results

Conclusions

Publications

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

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