A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease (original) (raw)
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Diabetes Care, 2017
This study tested the hypothesis that genetically raised hyperglycemia increases coronary artery disease (CAD) risk separately from the risk conferred by type 2 diabetes as a whole. RESEARCH DESIGN AND METHODS We conducted a Mendelian randomization (MR) analysis using summary-level statistics from the largest published meta-analyses of genome-wide association studies (GWAS) for fasting glucose (FG) (n = 133,010 participants free of diabetes) and CAD (n = 63,746 case subjects and 130,681 control subjects) of predominantly European ancestry. FG-increasing variants associated with type 2 diabetes from the largest GWAS for type 2 diabetes were excluded. Variants with pleiotropic effects on other CAD risk factors (blood lipids, blood pressure, and obesity) were excluded using summary-level data from the largest published GWAS. Data from the Framingham Heart Study were used to validate the MR instrument and to build an FG genetic risk score (GRS). RESULTS In an instrumental variable analysis comprising 12 FG-raising variants, a 1 mmol/L increase in FG revealed an effect-size estimate of 1.43 CAD odds (95% CI 1.14-1.79). The association was preserved after excluding variants for heterogeneity and pleiotropic effects on other CAD risk factors (odds ratio [OR] 1.33 [95% CI 1.02-1.73]). The 12 FG-increasing variants did not significantly increase type 2 diabetes risk (OR 1.05 [95% CI 0.91-1.23]), and its prevalence was constant across FG GRS quintiles (P = 0.72). CONCLUSIONS Our data support that genetic predisposition to hyperglycemia raises the odds of CAD separately from type 2 diabetes and other CAD risk factors. These findings suggest that modulating glycemia may provide cardiovascular benefit. Diabetes, a disease characterized by persistent hyperglycemia, is a global public health crisis affecting 415 million people worldwide (1). Prospective epidemiological data have suggested that individuals with type 2 diabetes have a higher incidence of coronary artery disease (CAD) than those without type 2 diabetes, leading to the consideration of type 2 diabetes as a heart disease risk equivalent for the prediction of future CAD (2). However, type 2 diabetes is a complex disease, typically
Methods Risk score calculation (second risk score analysis): As explained by Voight et al (1) and Ehret et al (2) we defined genetic risk scores in the following way: Using a set of m SNPs, for the i-th SNP in the j-th individual denote xij as the 0/1/2 coded genotype (for directly genotyped SNPs) or expected allele dosage (which takes real values between 0.0 and 2.0 for imputed SNPs). Using results from multiple GWAS, define the set of regression coefficients to be w1, w2, ..., wm. Then the risk score for subject j is defined to be (1) sj = s0 + w1 x1j + w2 x2j + ... + wm xmj, where s0 is the intercept. In all our analyses, we specify the coefficients w1, w2, ..., wm to be the effect sizes, in standard deviation units per coded allele, estimated in single SNP analyses of T2DM.We also note that, when considering multiple SNPs that are in linkage equilibrium with each other, and small effect sizes per SNP, effect sizes estimated jointly for all SNPs using a multiple regression model are effectively identical to those estimated in a series of single SNP regression models. Thus regression on the risk score can be reconstructed from regressions on each of the m SNPs in turn, without further access to individual-level data. The calculations involved are of the same type as for meta-analysis; the coefficient of the risk score is a weighted mean of the per-SNP regression coefficients, where each is weighted by its corresponding wi. The estimated variance of the risk score is given by similarly weighting the estimated variances
Cardiovascular health, genetic predisposition, and lifetime risk of type 2 diabetes
European Journal of Preventive Cardiology, 2021
Aims Data on the lifetime risk of type 2 diabetes (T2D) incidence across different cardiovascular health (CVH) categories are scarce. Moreover, it remains unclear whether a genetic predisposition modifies this association. Methods and results Using data from the prospective population-based Rotterdam Study, a CVH score (body mass index, blood pressure, total cholesterol, smoking status, diet, and physical activity) was calculated and further categorized at baseline. Genetic predisposition to T2D was assessed and divided into tertiles by creating a genetic risk score (GRS). We estimated the lifetime risk for T2D within different CVH and GRS categories. Among 5993 individuals free of T2D at baseline [mean (standard deviation) age, 69.1 (8.5) years; 58% female], 869 individuals developed T2D during follow-up. At age 55 years, the remaining lifetime risk of T2D was 22.6% (95% CI: 19.4–25.8) for ideal, 28.3% (25.8–30.8) for intermediate, and 32.6% (29.0–36.2) for poor CVH. After further ...
Diabetes, 2011
OBJECTIVE The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52–0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numb...
Diabetes, 2016
This study focused on resolving the relationship between body mass index (BMI) and type 2 diabetes. The availability of multiple variants associated with BMI offers a new chance to resolve the true causal effect of BMI on T2D, however the properties of these associations and their validity as genetic instruments need to be considered alongside established and new methods for undertaking Mendelian randomisation. We explore the potential for pleiotropic genetic variants to generate bias, revise existing estimates and illustrate value in new analysis methods. A two-sample Mendelian randomisation (MR) approach with 96 genetic variants was employed using three different analysis methods, two of which (MR-Egger and the weighted median) have been developed specifically to address problems of invalid instrumental variables. We estimate an odds ratio for type 2 diabetes per unit increase in BMI (kg/m(2)) of between 1.19 and 1.38, with the most stable estimate using all instruments and a weig...
Polygenic risk for coronary heart disease acts through atherosclerosis in type 2 diabetes
Cardiovascular Diabetology
Background Type 2 diabetes increases the risk of coronary heart disease (CHD), yet the mechanisms involved remain poorly described. Polygenic risk scores (PRS) provide an opportunity to understand risk factors since they reflect etiologic pathways from the entire genome. We therefore tested whether a PRS for CHD influenced risk of CHD in individuals with type 2 diabetes and which risk factors were associated with this PRS. Methods We tested the association of a CHD PRS with CHD and its traditional clinical risk factors amongst individuals with type 2 diabetes in UK Biobank (N = 21,102). We next tested the association of the CHD PRS with atherosclerotic burden in a cohort of 352 genome-wide genotyped participants with type 2 diabetes who had undergone coronary angiograms. Results In the UK Biobank we found that the CHD PRS was strongly associated with CHD amongst individuals with type 2 diabetes (OR per standard deviation increase = 1.50; p = 1.5 × 10− 59). But this CHD PRS was, at b...
Diabetes care, 2018
We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, = 4 × 10, and HR per SD 1.35, 95% CI 1.16-1.58, = 2 × 10, respectively). This associatio...
Deciphering correlation and causation in risk factors for heart disease with Mendelian randomization
Journal of Emerging Investigators
In this analysis, we studied the use of Mendelian randomization to identify the risk factors of coronary artery disease (CAD), a major cause of cardiovascular disease. Identifying risk factors of CAD are critical to understanding and managing the disease. Our analysis combined results from 28 genetic analyses from 12 unique studies. For each genetic variation, we obtained the variant ID, chromosome, base-pair position, reference and alternative alleles of the genetic variation, and estimated effect and p-value of the genetic variation on the outcome. We hypothesized that traits which are correlated with CAD outcomes will be causally associated with CAD risk in a genetic Mendelian randomization analysis. Our analysis showed that several traits such as blood pressure readings (systolic, OR 0.51 (95% CI: 0.34-0.69), p-value = 5.4x10-9) and (diastolic, OR 0.56 (95% CI: 0.41-0.71), p-value = 7.6x10-14), LDL cholesterol levels (OR 0.54 (95% CI: 0.47-0.60), p-value = 4.4x10-56), and BMI (O...
Diabetes, 2019
Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (Pinteraction > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL chol...
Cardiovascular diabetology, 2016
The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits. Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox's Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185). Overall, 10-year CHD risk ranged from 2-72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plu...