Abstract
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.
Highlights
The worldwide prevalence of type 2 diabetes (T2D) has increased dramatically over the last few decades, with an estimated 400 million affected individuals in 20151
Associations with T2D and coronary heart disease (CHD) Using conventional Inverse-variance weighted (IVW) Mendelian randomisation (MR) in 26,676 T2D cases and 132,532 controls in DIAGRAM consortium, a one-SD higher estimated heel bone mineral density (eBMD) instrumented by 232 single nucleotide polymorphisms (SNPs) present in both of DIAGRAM and CARDIoGRAMplusC4D genome wide association study (GWAS) consortia was associated with an 8% (95%CI: 2% to 14%, p=0.012) higher risk of T2D and 5% (95%CI: 0% to 10%, p=0.034) higher risk of CHD (Figure 2, Supplementary Figure 3 and Supplementary Figure 4)
Reverse associations of genetic liability to T2D and CHD with eBMD Using genetic variants previously identified for T2D (94 SNPs) and CHD (52 SNPs) as instrumental variables, we found no convincing evidence of a causal relationship with eBMD, providing no support for reverse causality of T2D or CHD with eBMD (Supplementary Table 11 and Supplementary Table 12)
Summary
The worldwide prevalence of type 2 diabetes (T2D) has increased dramatically over the last few decades, with an estimated 400 million affected individuals in 20151. Observational studies have reported associations between bone mineral density (BMD) and risk of T2D, with studies showing that BMD is higher in individuals with diabetes than in individuals free from diabetes[7,8,9,10,11]. 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. 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
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