Relationship Between Serum Amino Acid Levels and Bone Mineral Density: A Mendelian Randomization Study

BackgroundThis study aimed to explore the association between serum amino acids (AAs) levels and bone mineral density (BMD).MethodsWe performed a two-sample Mendelian randomization (MR) analysis to analyze the associations between the levels of eight AAs and BMD values by using summary-level genome-wide association study (GWAS) data. We applied the MR Steiger filtering method and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test to check for and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. The associations were estimated with the inverse variance weighted (IVW), MR-Egger, weighted median and MR Robust Adjusted Profile Score (MR.RAPS) methods.ResultsOur study found that genetically increased isoleucine (Ile) [IVW: effect = 0.1601, 95% confidence interval (CI) = 0.0604 ~ 0.2597, p = 0.0016] and valine (Val) levels (IVW: effect = 0.0953, 95% CI = 0.0251 ~ 0.1655, p = 0.0078) were positively associated with total body BMD (TB-BMD). The results also revealed that genetically increased tyrosine (Tyr) levels were negatively associated with TB-BMD (IVW: effect = -0.1091, 95% CI = -0.1863 ~ -0.0320, p = 0.0055).ConclusionsIn this study, associations between serum AA levels and BMD were established. These findings underscore the important role that serum AAs play in the development of osteoporosis and provide evidence that osteoporosis can be prevented and treated by the intake of certain AAs.

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Parathyroid Hormone and Bone Mineral Density: A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa579 ◽

2020 ◽

Vol 105 (11) ◽

Author(s):

Zihao Qu ◽

Fangkun Yang ◽

Jianqiao Hong ◽

Wei Wang ◽

Shigui Yan

Keyword(s):

Bone Mineral Density ◽

Parathyroid Hormone ◽

Bone Mineral ◽

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Age Groups ◽

Mineral Density ◽

Serum Pth

Abstract Purpose Accumulating evidence implicates parathyroid hormone (PTH) in the development of osteoporosis. However, the causal effect of PTH on bone mineral density (BMD) remains unclear. Thus, this study is aimed at exploring the association between the concentrations of serum PTH and BMD. Methods The instrumental variables for PTH were selected from a large-scale genome-wide association study (GWAS; n = 29 155). Outcomes included BMD of the forearm (FA; n = 8143), femoral neck (FN; n = 33 297), lumbar spine (LS; n = 32 735), heel (HL; n = 394 929), and risk of fractures in these bones (n = 361 194). Furthermore, the BMD of 5 different age groups: 15 years or younger (n = 11 807), 15–30 (n = 4180), 30–45 (n = 10 062), 45–60 (n = 18 805), and 60 years or older (n = 22 504) were extracted from a GWAS meta-analysis study. The analyses were performed using the 2-sample Mendelian randomization method. Results Mendelian randomization analysis revealed that the level of serum PTH was inversely associated with BMD of FA (95% CI: -0.763 to -0.016), FN (95% CI: -0.669 to -0.304), and LS (95% CI: -0.667 to -0.243). A causal relationship between serum PTH levels and BMD was observed in individuals aged 30–45 (95% CI: -0.888 to -0.166), 45–60 (95% CI: -0.758 to -0.232), and over 60 years (95% CI: -0.649 to -0.163). Main Conclusions This study demonstrated that the concentrations of serum PTH is inversely associated with BMD of several bones. Further analysis revealed site- and age-specific correlations between serum PTH levels and BMD, which implies that the levels of serum PTH contribute to the development of osteoporosis.

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Matrix Metalloproteinases in Relation to Bone Mineral Density: A Two-Sample Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.754795 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xin Lv ◽

Pengfei Wu ◽

Shipeng Xiao ◽

Wan Zhang ◽

Yawei Li ◽

...

Keyword(s):

Bone Mineral Density ◽

Lumbar Spine ◽

Matrix Metalloproteinases ◽

Femoral Neck ◽

Bone Mineral ◽

Mendelian Randomization ◽

Causal Effects ◽

Sensitivity Analyses ◽

Mineral Density ◽

Inverse Variance

Background: We aimed at investigating causal associations between matrix metalloproteinases (MMPs) and bone mineral density (BMD) by the Mendelian randomization (MR) analysis.Methods: From genome-wide association studies of European ancestry, we selected instrumental variables for MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12. Accordingly, we retrieved summary statistics of three site-specific BMD, namely, forearm, femoral neck, and lumbar spine. We conducted an inverse variance weighted MR as the primary method to compute overall effects from multiple instruments, while additional MR approaches and sensitivity analyses were implemented. Bonferroni-adjusted significance threshold was set at p < 0.05/18 = 0.003.Results: Totally, there was no evidence for causal effects of genetically-predicted levels of MMPs on BMD measurement at three common sites. MR results indicated that there were no causal associations of circulating MMPs with forearm BMD (all p ≥ 0.023) by the inverse variance weighted method. Similarly, there were no causal effects of MMPs on femoral neck BMD (all p ≥ 0.120) and MR results did not support causal relationships between MMPs and lumbar spine BMD (all p ≥ 0.017). Multiple sensitivity analyses suggested the robustness of MR results, which were less likely to be biased by unbalanced pleiotropy or evident heterogeneity.Conclusion: We found no evidence for the causal relationship between MMPs and BMD in the European population.

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Identification of New Genes and Loci Associated With Bone Mineral Density Based on Mendelian Randomization

Frontiers in Genetics ◽

10.3389/fgene.2021.728563 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yijun Liu ◽

Guang Jin ◽

Xue Wang ◽

Ying Dong ◽

Fupeng Ding

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Rare Variants ◽

Mendelian Randomization ◽

Association Studies ◽

Osteoporotic Fractures ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

New Genes

Bone mineral density (BMD) is a complex and highly hereditary trait that can lead to osteoporotic fractures. It is estimated that BMD is mainly affected by genetic factors (about 85%). BMD has been reported to be associated with both common and rare variants, and numerous loci related to BMD have been identified by genome-wide association studies (GWAS). We systematically integrated expression quantitative trait loci (eQTL) data with GWAS summary statistical data. We mainly focused on the loci, which can affect gene expression, so Summary data-based Mendelian randomization (SMR) analysis was implemented to investigate new genes and loci associated with BMD. We identified 12,477 single-nucleotide polymorphisms (SNPs) regulating 564 genes, which are associated with BMD. The genetic mechanism we detected could make a contribution in the density of BMD in individuals and play an important role in understanding the pathophysiology of cataclasis.

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Impact of serum calcium levels on local and total body bone mineral density: A Mendelian randomization study and an age stratum analysis

10.1101/737585 ◽

2019 ◽

Author(s):

Jing-yi Sun ◽

Haihua Zhang ◽

Yan Zhang ◽

Longcai Wang ◽

Jin Rok Oh ◽

...

Keyword(s):

Bone Mineral Density ◽

Lumbar Spine ◽

Femoral Neck ◽

Bone Mineral ◽

Serum Calcium ◽

Large Scale ◽

Mendelian Randomization ◽

Mineral Density ◽

Gwas Dataset ◽

Total Body

AbstractObjectivesUntil recently, randomized controlled trials and meta-analyses have not demonstrated convincing conclusions regarding the association of calcium intake with bone mineral density (BMD). Until now, it remains unclear whether high serum calcium levels are causally associated with BMD. This study aimed to investigate the genetic association between serum calcium levels and BMD using a large-scale serum calcium GWAS dataset and four large-scale BMD GWAS datasets in individuals of European descent.MethodsWe performed a Mendelian randomization study to investigate the association of increased serum calcium levels with BMD using a large-scale serum calcium genome-wide association study (GWAS) dataset (including up to 61,079 individuals) and four large-scale BMD GWAS datasets (including minimum 4,180 individuals and maximum 142,487 individuals) regarding the total body, forearm, femoral neck, lumbar spine, and heel BMD. Here, we selected three Mendelian randomization methods including inverse-variance weighted meta-analysis (IVW), weighted median, and MR-Egger.ResultsIn specific site analysis, we found that increased serum calcium levels could reduce BMD at forearm (OR=0.59, 95% CI: 0.36-0.95, P=0.029) and lumbar spine (OR=0.65, 95% CI: 0.49-0.86, P=0.002). We did not identify any suggestive association of genetically increased serum calcium levels with BMD of total body, femoral neck, and heel BMD. In specific age stratum analysis, we found that genetically increased serum calcium levels were statistically significantly associated with reduced total body BMD in age stratum 60 or more years (OR=0.58, 95% CI: 0.41-0.82, P=0.002).ConclusionsWe provide genetic evidence that increased serum calcium levels could not improve BMD in the general population. The elevated serum calcium levels in generally healthy populations, especially adults older than 60 years, may even reduce the BMD, and further cause osteoporosis.

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Positive effects of low LDL-C and statins on bone mineral density: an integrated epidemiological observation analysis and Mendelian randomization study

International Journal of Epidemiology ◽

10.1093/ije/dyz145 ◽

2019 ◽

Vol 49 (4) ◽

pp. 1221-1235 ◽

Cited By ~ 6

Author(s):

Gloria Hoi-Yee Li ◽

Ching-Lung Cheung ◽

Philip Chun-Ming Au ◽

Kathryn Choon-Beng Tan ◽

Ian Chi-Kei Wong ◽

...

Keyword(s):

Bone Mineral Density ◽

Femoral Neck ◽

Bone Mineral ◽

Large Scale ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Nhanes Iii ◽

Mineral Density ◽

Positive Effects ◽

Epidemiological Observation

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to bone mineral density (BMD) and assess the effects of LDL-C-lowering drugs on BMD. Methods Association between blood lipid levels and BMD was examined by epidemiological observation analyses in a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (GWAS) of blood lipids (n = 188 577), total body BMD (TB-BMD) (n = 66 628) and estimated BMD (eBMD) (n= 142 487), was performed to infer causality between LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs’ effects on BMD. Results In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 − 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 − 0.074]; P = 0.038} and eBMD [0.076 (0.042 − 0.111); P = 1.20x10−5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 − 0.066); P = 0.034]. Statins’ LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 − 0.316); P = 9.600x10−3] and eBMD [0.143 (0.062 − 0.223); P = 5.165x10−4]. Conclusions Negative causal association exists between LDL-C level and BMD. Statins’ LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.

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