Assessing the Associations of Blood Metabolites With Osteoporosis: A Mendelian Randomization Study

Abstract

Context: Osteoporosis is a metabolic bone disease. The effect of blood metabolites on the development of osteoporosis remains elusive.Objective: To explore the relationship between blood metabolites and osteoporosis.Design and Methods: We used 2286 unrelated white subjects for the discovery samples and 3143 unrelated white subjects from the Framingham Heart Study (FHS) for the replication samples. The bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a reported whole-genome sequencing study. For each subject, the genetic risk score of the metabolite was calculated from the genotype data of the metabolite-associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential effect of blood metabolites on the variations in bone phenotypes; 10,000 permutations were conducted to calculate the empirical P value and false discovery rate.Results: We analyzed 481 blood metabolites. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol (P discovery , 0.0001; P replication = 0.0361), inosine (P discovery = 0.0018; P replication = 0.0256), theophylline (P discovery = 0.0048; P replication = 0.0433, gamma-glutamyl methionine (P discovery = 0.0047; P replication = 0.0471), 1-linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6; P discovery = 0.0018; P replication = 0.0390), and X-12127 (P discovery = 0.0002; P replication = 0.0249). Conclusions:Our results suggest a modest effect of blood metabolites on the variations of BMD and identified several candidate blood metabolites for osteoporosis. (J Clin Endocrinol Metab 103: 1850-1855 O steoporosis is a metabolic bone disease, characterized as low bone mass and increased bone fragility. It has been reported that currently .40 million people are at risk of bone fractures, and the incidence of osteoporotic fractures is increasing rapidly in the United States (1). Bone mineral density (BMD) is commonly used to 1850https://academic.oup.com/jcem

A road map for understanding molecular and genetic determinants of osteoporosis

“…For example, all the current studies ( Supplementary Table 7) are cross-sectional. Although two studies used Mendelian randomization (BOX 1) to provide potential evidence for a causal relationship of identified metabolites with osteoporosis 110,111 , well designed longitudinal studies are necessary. In addition, potential sex differences in osteoporosis-related metabolites should be investigated, as most published studies only include women.…”

Metabolic Alterations in Older Women With Low Bone Mineral Density Supplemented With Lactobacillus reuteri

“…Untargeted metabolomics have provided an opportunity to investigate the global metabolic changes in human populations. (11,12) Although the existing metabolomic studies related to osteoporosis had been performed in rats and human populations, (13)(14)(15)(16) the effects of probiotic supplementation on human bone metabolism have not been explored. Therefore, we investigated the effect of daily supplementation with L. reuteri or placebo on serum metabolomic profiles in older women included in a one-year randomized controlled trial (RCT), in a non-predefined post hoc analysis.…”

Metabolomic profiles associated with bone mineral density in US Caucasian women

“…However, the existing metabolomics studies of osteoporosis in humans are limited to East Asian and European populations, mainly including postmenopausal women [ 8 – 11 ]. A Mendelian randomization study used the genome-phenotype association data from the US population and metabolomics-phenotype association data from the UK and indirectly identified some metabolites associated with BMD [ 12 ]. Although promising findings were obtained from these studies, it is still unclear if the findings could be generalized to other race/ethnicity populations since metabolomic profiles have strong genetic determination and are significantly influenced by age and menopause status [ 13 , 14 ].…”