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

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.

SUBMITTER: Gan W

PROVIDER: S-EPMC5606062 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Gan Wei W Clarke Robert J RJ Mahajan Anubha A Kulohoma Benard B Kitajima Hidetoshi H Robertson Neil R NR Rayner N William NW Walters Robin G RG Holmes Michael V MV Chen Zhengming Z McCarthy Mark I MI

Wellcome open research 20170822

<b>Background:</b> 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. <b>Methods:</b> We identified 235 independent single nucleotide polymorphisms (SNPs) asso ...[more]

PMID: 28989980

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Project description:BackgroundRecently, the association between inflammatory bowel disease (including ulcerative colitis and Crohn's disease) and BMD has attracted great interest in the research community. However, the results of the published epidemiological observational studies on the relationship between inflammatory bowel disease and BMD are still inconclusive. Here, we performed a two-sample Mendelian randomization analysis to investigate the causal link between inflammatory bowel disease and level of BMD using publically available GWAS summary statistics.MethodsA series of quality control steps were taken in our analysis to select eligible instrumental SNPs which were strongly associated with exposure. To make the conclusions more robust and reliable, we utilized several robust analytical methods (inverse-variance weighting, MR-PRESSO method, mode-based estimate method, weighted median, MR-Egger regression, and MR.RAPS method) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on BMD. Outlier variants identified by the MR-PRESSO outlier test were removed step-by-step to reduce heterogeneity and the effect of horizontal pleiotropy.ResultsOur two-sample Mendelian randomization analysis with two groups of exposure GWAS summary statistics and four groups of outcome GWAS summary statistics suggested a definitively causal effect of genetically predicted ulcerative colitis on TB-BMD and FA-BMD but not on FN-BMD or LS-BMD (after Bonferroni correction), and we merely determined a causal effect of Crohn's disease on FN-BMD but not on the others, which was somewhat inconsistent with many published observational researches. The causal effect of inflammatory bowel disease on TB-BMD was significant and robust but not on FA-BMD, FN-BMD, and LS-BMD, which might result from the cumulative effect of ulcerative colitis and Crohn's disease on BMDs.ConclusionsOur Mendelian randomization analysis supported the causal effect of ulcerative colitis on TB-BMD and FA-BMD. As to Crohn's disease, only the definitively causal effect of it on decreased FN-BMD was observed. Updated MR analysis is warranted to confirm our findings when a more advanced method to get less biased estimates and better precision or GWAS summary data with more ulcerative colitis and Crohn's disease patients was available.

Project description:BackgroundIn observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two.MethodsGenetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results.ResultsAfter Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent.ConclusionThe results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.

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

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

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