Gan Wei, Clarke Robert J, Mahajan Anubha, Kulohoma Benard, Kitajima Hidetoshi, Robertson Neil R, Rayner N William, Walters Robin G, Holmes Michael V, Chen Zhengming, McCarthy Mark I
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, OX3 7LE, UK.
Wellcome Open Res. 2017 Aug 22;2:68. doi: 10.12688/wellcomeopenres.12288.1. eCollection 2017.
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. We identified 235 independent single nucleotide polymorphisms (SNPs) associated at <5×10 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. Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm ) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; =0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; =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. These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.
观察性研究表明，骨矿物质密度增加与2型糖尿病（T2D）风险较高相关，但与冠心病（CHD）风险的关系尚不清楚。此外，骨矿物质密度增加与T2D和CHD之间因果关系的实质性不确定性仍然存在，这可以通过孟德尔随机化研究来评估。我们在英国生物银行研究的116,501名个体中确定了235个与估计的足跟骨矿物质密度（eBMD）相关的独立单核苷酸多态性（SNP），其与<5×10相关，占eBMD方差的13.9%。对于每个与eBMD相关的SNP，我们从T2D（DIAGRAM：n = 26,676例T2D病例和132,532例对照）和CHD（CARDIoGRAMplusC4D：n = 60,801例CHD病例和123,504例对照）的最大可用全基因组关联研究（GWAS）中提取效应估计值。使用几种孟德尔随机化方法的两样本设计用于研究eBMD与T2D和CHD风险的因果关系。此外，我们探讨了由235个SNP作为工具变量的eBMD与12种心血管和代谢危险因素之间的关系。最后，我们进行了反向孟德尔随机化分析以研究反向因果关系。遗传工具化的eBMD每增加一个标准差（相当于0.14 g/cm）与T2D风险增加8%相关（优势比[OR] 1.08；95%置信区间[CI]：1.02至1.14；P = 0.012），与CHD风险增加5%相关（OR 1.05；95%CI：1.00至1.10；P = 0.034）。使用几种不同孟德尔随机化方法的敏感性分析获得了一致的结果。eBMD的等效增加也与较低的高密度脂蛋白胆固醇血浆水平和增加的胰岛素抵抗相关。使用94个T2D SNP或52个CHD SNP进行的反向孟德尔随机化未显示与eBMD存在反向因果关系的证据。这些发现表明骨矿物质密度升高与T2D和CHD风险之间存在因果关系。
