Dataset Information

Association of type 2 Diabetes Mellitus and bone mineral density: a two-sample Mendelian randomization study.

ABSTRACT:

Background

Observational studies have suggested that type 2 Diabetes Mellitus (DM2) is a potentially modifiable risk factor for lower BMD, but the causal relationship is unclear. This study aimed to examine whether the association of DM2 with lower BMD levels was causal by using Mendelian randomization (MR) analyses.

Methods

We collected genome-wide association study data for DM2 and BMD of total body and different skeletal sites from the IEU database. Subsequently, we performed a two-sample Mendelian randomization analysis using the Two Sample MR package.

Results

We identified a positive association between DM2 risk (61,714 DM2 cases and 596,424 controls) and total BMD, and other skeletal sites BMD, such as femoral neck BMD, ultra-distal forearm BMD and heel BMD. However, non-significant trends were observed for the effects of DM2 on lumbar-spine BMD.

Conclusion

In two-sample MR analyses, there was positive causal relationship between DM2 and BMD in both overall samples. In summary, while observational analyses consistently indicate a strong association between DM2 and low BMD, our MR analysis introduces a nuanced perspective. Contrary to the robust association observed in observational studies, our MR analysis suggests a significant link between DM2 and elevated BMD.

SUBMITTER: Guan J

PROVIDER: S-EPMC10860277 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Association of type 2 Diabetes Mellitus and bone mineral density: a two-sample Mendelian randomization study.

Guan Jianbin J Liu Tao T Chen Hao H Yang Kaitan K

BMC musculoskeletal disorders 20240212 1

<h4>Background</h4>Observational studies have suggested that type 2 Diabetes Mellitus (DM2) is a potentially modifiable risk factor for lower BMD, but the causal relationship is unclear. This study aimed to examine whether the association of DM2 with lower BMD levels was causal by using Mendelian randomization (MR) analyses.<h4>Methods</h4>We collected genome-wide association study data for DM2 and BMD of total body and different skeletal sites from the IEU database. Subsequently, we performed a ...[more]

PMID: 38347501

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Project description:BackgroundPrevious studies have shown that bone mineral density (BMD) has a certain impact on scoliosis. However, up to now, there is no clear evidence that there is a causal association between the two. The aim of this study is to investigate whether there is a causal association between BMD at different body positions and scoliosis by two-sample Mendelian randomization (MR).MethodsGenetic variants (SNPS) strongly associated with BMD (total body BMD (TB-BMD), lumbar spine BMD (LS-BMD), femoral neck BMD (FN-BMD), heel BMD (HE-BMD), and forearm BMD (FA-BMD)) were extracted from GEFOS and genome-wide association analysis (GWAS) databases SNPs) were used as instrumental variables (IVs). Scoliosis was also selected from the Finnish database as the outcome. Inverse variance weighting (IVW) method was used as the main analysis method, and multiple sensitivity analysis was performed by combining weighted median, MR-Egger, MR Multi-effect residuals and outliers.ResultsIVW results showed that TB-BMD (OR = 0.83, 95%CI: 0.66-1.55 P = 0.13), LS-BMD (OR = 0.72, 95%CI: 0.52-0.99, P = 0.04), FN-BMD (OR = 0.74, 95%CI: 0.50-1.09, P = 0.13), FA-BMD (OR = 0.95,95%CI: 0.70-1.28, P = 0.75), HE-BMD (OR = 0.91, 95%CI: 0.77-1.08, P = 0.29). Sensitivity analyses showed no evidence of pleiotropy or heterogeneity (p > 0.05) (MR-PRESSO and Cochrane). The results were further validated by leave-one-out test and MR-Egger intercept, which confirmed the robustness of the study results.ConclusionIn conclusion, the present study demonstrates that the causal role of genetic prediction of scoliosis increases with decreasing lumbar BMD. There was no evidence that BMD at the remaining sites has a significant causal effect on scoliosis. Our results suggest that the lumbar spine BMD should be routinely measured in the population at high risk of scoliosis. If osteoporosis occurs, appropriate treatment should be given to reduce the incidence of scoliosis.Clinical trial numberNot applicable.

Project description:BackgroundRecent studies have reported that the gut microbiota is essential for preventing and delaying the progression of osteoporosis. Nonetheless, the causal relationship between the gut microbiota and the risk of osteoporosis has not been fully revealed.MethodsA two-sample Mendelian randomization (MR) analysis based on a large-scale genome-wide association study (GWAS) was conducted to investigate the causal relationship between the gut microbiota and bone mineral density (BMD). Instrumental variables for 211 gut microbiota taxa were obtained from the available GWAS meta-analysis (n = 18,340) conducted by the MiBioGen consortium. The summary-level data for BMD were from the Genetic Factors for Osteoporosis (GEFOS) Consortium, which involved a total of 32,735 individuals of European ancestry. The inverse variance-weighted (IVW) method was performed as a primary analysis to estimate the causal effect, and the robustness of the results was tested via sensitivity analyses by using multiple methods. Finally, a reverse MR analysis was applied to evaluate reverse causality.ResultsAccording to the IVW method, we found that nine, six, and eight genetically predicted gut microbiota were associated with lumbar spine (LS) BMD, forearm (FA) BMD, and femoral neck (FN) BMD, respectively. Among them, the higher genetically predicted Genus Prevotella9 level was correlated with increased LS-BMD [β = 0.125, 95% confidence interval (CI): 0.050-0.200, P = 0.001] and FA-BMD (β = 0.129, 95% CI: 0.007-0.251, P = 0.039). The higher level of genetically predicted Family Prevotellaceae was associated with increased FA-BMD (β = 0.154, 95% CI: 0.020-0.288, P = 0.025) and FN-BMD (β = 0.080, 95% CI: 0.015-0.145, P = 0.016). Consistent directional effects for all analyses were observed in both the MR-Egger and weighted median methods. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on BMD (P > 0.05). In reverse MR analysis, there was no evidence of reverse causality between LS-BMD, FA-BMD, and FN-BMD and gut microbiota (P > 0.05).ConclusionGenetic evidence suggested a causal relationship between the gut microbiota and BMD and identified specific bacterial taxa that regulate bone mass variation. Further exploration of the potential microbiota-related mechanisms of bone metabolism might provide new approaches for the prevention and treatment of osteoporosis.

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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.

Dataset Information

Association of type 2 Diabetes Mellitus and bone mineral density: a two-sample Mendelian randomization study.

Background

Methods

Results

Conclusion

Publications

Association of type 2 Diabetes Mellitus and bone mineral density: a two-sample Mendelian randomization study.

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