Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study

Zeng, Hailuan; Ge, Jike; Xu, Wenjie; Ma, Hui; Chen, Lingyan; Xia, Mingfeng; Pan, Baishen; Hao, Lin; Wang, Sijia; Gao, Xin

doi:10.1002/jbmr.4330

Cited by 31 publications

(25 citation statements)

References 62 publications

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“…Besides, some studies have suggested that SMM, not BFM, is highly associated with BMD, 27–31 while others have shown that BFM, not SMM, is a key contributor to BMD. 32 , 33 Still, other studies have found that both BFM and SMM are significant indicators of BMD. 34–36 Studies of BFM and BMD in childhood have also presented mixed results, reporting positive, 37 , 38 negative, 39 or null associations.…”

Section: Discussionmentioning

confidence: 97%

Novel Insight into the Relationship Between Muscle-Fat and Bone in Type 2 Diabetes Ranging from Normal Weight to Obesity

Wang¹,

Peng²,

Zhang³

et al. 2022

DMSO

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Objective Decreased bone mineral density (BMD) is a common complication in individuals with type 2 diabetes mellitus (T2DM). Body weight, mainly consisting of muscle and fat, is the main determinant of BMD and fracture risks but does not accurately describe nutritional status. Most studies suggest that skeletal muscle mass (SMM) promotes BMD, while body fat mass (BFM) decreases BMD. However, the combined effect of SMM and BFM on BMD is elusive. Thus, the study aims to explore the combined effect of fat and muscle by the ratio index SMM/BFM on BMD in T2DM. Methods BFM and SMM were measured by the bioelectrical impedance analysis (BIA) method among 593 T2DM individuals ranging from normal weight and obesity. BMD was analyzed by DXA. Novel non-linear generalized additive models (GAMs) were used as the statistical analysis method. Results The results demonstrated that BMD T score/Z score of both femur and lumbar vertebrae were significantly higher and waist–hip ratio (WHR) was significantly lower in the high SMM/BFM group of both normal weight and overweight groups in T2DM individuals. Hence, SMM/BFM might be a good factor indicating BMD in different weight ranges. Additionally, the relationship between muscle fat and BMD was not linear. Notably, this correlation was not influenced by hyperglycemia in T2DM since different analytic models adjusted with the age, gender, BMI and HbA1c were adopted in this study. Furthermore, the impact of trunk fat (central, visceral fat most) and non-trunk fat (peripheral, the sum of subcutaneous limb fat most) on BMD was inconsistent. BMD presented unlimited reduction with trunk BFM increasing, while sustaining minimal diminishment with non-trunk BFM accumulation. Conclusion Our study provided a novel viewpoint relationship between muscle-fat and bone, and SMM/BFM might be a potential biomarker for bone health and clinical treatments of diabetes and related metabolic syndromes.

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Section: Discussionmentioning

confidence: 97%

Novel Insight into the Relationship Between Muscle-Fat and Bone in Type 2 Diabetes Ranging from Normal Weight to Obesity

Wang¹,

Peng²,

Zhang³

et al. 2022

DMSO

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“…We followed the method suggested by S.Burgess et al (URL: http://mendelianrandomization.com/) to calculate the power when genetically predicting binary exposure. 26,27 We calculated beta 2 ×2×MAF×(1-MAF), where MAF indicates minor allele frequency, of each genetic instruments and the sum of the values was the coefficient of determination of exposure. Despite the limitation, this approach of using odds ratios as a proxy for prevalence ratio was necessary as genetic beta effect sizes were not scaled to prevalence increase of a unit of an exposure in GWAS.…”

Section: Methodsmentioning

confidence: 99%

Causal linkage of tobacco smoking with ageing traits: a Mendelian randomization analysis towards telomere attrition and frailty

Park

Kim

Lee

et al. 2022

Preprint

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Background: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects from tobacco smoking on various ageing traits is warranted. Methods: This Mendelian randomization (MR) analysis instrumented 377 genetic variants associated with being an ever smoker in a genome-wide significant level to test the causal estimates from tobacco smoking. The outcome data included 337,318 white British ancestry UK Biobank participants. Leukocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry determined physical activity degree were collected as ageing related outcomes. Summary-level MR by inverse variance weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger, was performed. Results: Summary-level MR analysis indicated that higher genetic predisposition for tobacco smoking was significantly associated with shorter leukocyte telomere length [2-fold prevalence increase in smoking towards standardized Z-score, -0.041 (-0.054, -0.028)], lower appendicular lean mass index [-0.007 (-0.010, -0.005)], slower walking pace [ordinal category, -0.047 (-0.054, -0.033)], and lower time spent on moderate-to-vigorous physical activity [hours per week, -0.39 (-0.56, -0.23). The causal estimates were nonsignificant towards handgrip strength phenotype [kg, 0.074 (-0.055, 0.204)]. Pleiotropy-robust MR results generally supported the main causal estimates. Conclusion: Genetically predicted tobacco smoking is significantly associated with worse ageing phenotypes. Healthcare providers may continue to reduce tobacco use which may be helpful to reduce the burden related to ageing and frailty.

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“…Post hoc power calculation for MR analysis was performed by an online tool (URL: https://sb452.shinyapps. io/power/), followed the method suggested by S. Burgess (URL: http://mendelianrandomization.com/) [33,34]. We calculated beta^2*2*MAF*(1-MAF), where MAF indicates minor allele frequency, of each instrumented SNP and summed the values for the coefficient necessary for the power calculator.…”

Section: Summary-level Mr Analysis Methodsmentioning

confidence: 99%

Causal effects of atrial fibrillation on brain white and gray matter volume: a Mendelian randomization study

Park

Lee

Kim

et al. 2021

BMC Med

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Background Atrial fibrillation (AF) and brain volume loss are prevalent in older individuals. We aimed to assess the causal effect of atrial fibrillation on brain volume phenotypes by Mendelian randomization (MR) analysis. Methods The genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis (15,993 AF patients and 113,719 controls of European ancestry). The outcome summary statistics for head-size-normalized white or gray matter volume measured by magnetic resonance imaging were provided by a previous GWAS of 33,224 white British participants in the UK Biobank. Two-sample MR by the inverse variance–weighted method was performed, supported by pleiotropy-robust MR sensitivity analysis. The causal estimates for the effect of AF on ischemic stroke were also investigated in a dataset that included the findings from the MEGASTROKE study (34,217 stroke patients and 406,111 controls of European ancestry). The direct effects of AF on brain volume phenotypes adjusted for the mediating effect of ischemic stroke were studied by multivariable MR. Results A higher genetic predisposition for AF was significantly associated with lower grey matter volume [beta −0.040, standard error (SE) 0.017, P=0.017], supported by pleiotropy-robust MR sensitivity analysis. Significant causal estimates were identified for the effect of AF on ischemic stroke (beta 0.188, SE 0.026, P=1.03E−12). The total effect of AF on lower brain grey matter volume was attenuated by adjusting for the effect of ischemic stroke (direct effects, beta −0.022, SE 0.033, P=0.528), suggesting that ischemic stroke is a mediator of the identified causal pathway. The causal estimates were nonsignificant for effects on brain white matter volume as an outcome. Conclusions This study identified that genetic predisposition for AF is significantly associated with lower gray matter volume but not white matter volume. The results indicated that the identified total effect of AF on gray matter volume may be mediated by ischemic stroke.

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Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study

Cited by 31 publications

References 62 publications

Novel Insight into the Relationship Between Muscle-Fat and Bone in Type 2 Diabetes Ranging from Normal Weight to Obesity

Novel Insight into the Relationship Between Muscle-Fat and Bone in Type 2 Diabetes Ranging from Normal Weight to Obesity

Causal linkage of tobacco smoking with ageing traits: a Mendelian randomization analysis towards telomere attrition and frailty

Causal effects of atrial fibrillation on brain white and gray matter volume: a Mendelian randomization study

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