Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study

Wei Gan; Robert J Clarke; Anubha Mahajan; Benard Kulohoma; Hidetoshi Kitajima; Neil R Robertson; N William Rayner; Robin G Walters; Michael V Holmes; Zhengming Chen; Mark I McCarthy

doi:10.12688/wellcomeopenres.12288.1

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study

Wellcome Open Res. 2017 Aug 22:2:68. doi: 10.12688/wellcomeopenres.12288.1. eCollection 2017.

Authors

Wei Gan^{1

2}, Robert J Clarke^{3

4}, Anubha Mahajan^{1

2}, Benard Kulohoma^{1

5}, Hidetoshi Kitajima¹, Neil R Robertson^{1

2}, N William Rayner^{1

2}, Robin G Walters^{3

4}, Michael V Holmes^{3

4

6

7}, Zhengming Chen^{3

4}, Mark I McCarthy^{1

2

6}

Affiliations

¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
² Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, OX3 7LE, UK.
³ Big Data Institute, University of Oxford, Oxford, OX3 7FZ, UK.
⁴ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
⁵ Centre for Biotechnology and Bioinformatics, University of Nairobi, Nairobi, Kenya.
⁶ National Institute of Health Research Oxford Biomedical Research Centre, Oxford, OX3 7LE, UK.
⁷ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, OX3 7LF, UK.

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.

Keywords: Bone mineral density; Cardiovascular disease; Causality; Coronary artery disease; Mendelian randomization; Type 2 diabetes; UK biobank; insulin resistance.

Abstract

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