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

ABSTRACT: 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.

SUBMITTER: Ahmad OS

PROVIDER: S-EPMC4458864 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Ahmad Omar S OS Morris John A JA Mujammami Muhammad M Forgetta Vincenzo V Leong Aaron A Li Rui R Turgeon Maxime M Greenwood Celia M T CM Thanassoulis George G Meigs James B JB Sladek Robert R Richards J Brent JB

Nature communications 20150528

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 CH ...[more]

PMID: 26017687

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Project description:Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies. Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at p<5×10 -8 with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm 2) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

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

Publications

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

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