A Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease

In observational studies, type-2 diabetes (T2D) is associated with an increased risk of coronary heart disease (CHD), yet interventional trials have shown no clear effect of glucose-lowering on CHD. Confounding may have therefore influenced these observational estimates. Here we use Mendelian randomization to obtain unconfounded estimates of the influence of T2D and fasting glucose (FG) on CHD risk. Using multiple genetic variants associated with T2D and FG, we find that risk of T2D increases CHD risk (odds ratio (OR)=1.11 (1.05–1.17), per unit increase in odds of T2D, P=8.8 × 10−5; using data from 34,840/114,981 T2D cases/controls and 63,746/130,681 CHD cases/controls). FG in non-diabetic individuals tends to increase CHD risk (OR=1.15 (1.00–1.32), per mmol·per l, P=0.05; 133,010 non-diabetic individuals and 63,746/130,681 CHD cases/controls). These findings provide evidence supporting a causal relationship between T2D and CHD and suggest that long-term trials may be required to discern the effects of T2D therapies on CHD risk.

), the Forest plot shows the estimate of the effect of the HbA1c risk allele upon CHD risk, as assessed for each SNP. Also shown for each SNP is the 95% confidence interval (black line segment) of the estimate and the inverse-variance weight (% proportional to the size of the grey square) in the random-effects meta-analysis.

Supplementary Note 1. Typical effects risk-increasing genetic variants.
In this section, we present the random-effects estimates of the typical effect of risk-increasing genetic variants for T2D, fasting glucose, and hemoglobin A1c (HbA1c). Because of the high degree of heterogeneity in effect sizes between variants for each of the exposure traits, the random-effects estimates for the typical genetic effect on each exposure trait approaches that of an unweighted average of the individual effect-sizes.
We used a random-effects model to estimate the effect of a typical T2D risk-increasing variant upon T2D risk. Using the full set of genome-wide significant T2D risk-increasing alleles (n=37), we estimated that the typical odds ratio of a T2D risk-increasing variant upon T2D risk to be OR = 1.11 per allele (95%CI: 1.09-1.12); p = 1.0x10 -49 for the MR analysis; I 2 = 88.9 (95%CI: 86-92).
( Supplementary Table 1, Supplementary Fig. 1 Table 1, Supplementary Fig. 2). As expected, the unweighted average effect for the both the full set of 33 variants and the set of 24 nonpleiotropic variants yielded estimates similar to the random-effects estimates.
( Supplementary Table 1, Supplementary Fig. 3). As expected, the unweighted average effect for the both the full set of 11 variants and the subset of 9 non-pleiotropic variants yielded estimates similar to the random-effects estimates.

Supplementary Note 2. Hemoglobin A1c and CHD risk
We identified 11 genetic variants found to be significantly associated (P < 5x10 -8 ) with HbA1c levels (Supplementary Table 5, Supplementary Fig. 4) using data from the MAGIC consortium's most recent GWAS (n = 133,010 non-diabetic individuals). 5 Of these variants, 9 were found to be free of pleiotropy.
Using the full set of genome-wide significant variants (n=11), we carried out a random-effects meta-analysis of the instrumental-variables estimates associated with each SNP. This yielded an  Fig. 5). Neither the analysis using the full set of significant variants, nor the analysis using the subset of non-pleiotropic variants produced results that were statistically significant at the 95% confidence level. Fixed-effects models yielded non-significant estimates similar to those of the random-effects models (Supplementary Table 7).