Association between single nucleotide polymorphisms of estrogen receptor α gene and efficacy of HRT on bone mineral density in post-menopausal Japanese women

Abstract Context Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to non-users, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective To investigate potential single nucleotide polymorphisms (SNPs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry, and genetic data from the Framingham Heart Study’s (FHS) Offspring Cohort. We then sought to validate our top four genetic findings using data from the Rotterdam Study, the BPROOF Study, the MOFS, and the Hertfordshire Cohort Study. Design We used sex-stratified linear mixed models to determine SNPs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top single nucleotide polymorphisms (SNPs) from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNPs may impact FN BMD. Results One polymorphism (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these polymorphisms, which further validated our findings. Conclusions This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.

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Association of single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene (POMC) with low bone mineral density in adult women.

10.31234/osf.io/8xpm5 ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Bone Mineral Density ◽

Single Nucleotide Polymorphisms ◽

Bone Mineral ◽

Promoter Region ◽

Total Cholesterol Level ◽

Adult Women ◽

Nucleotide Polymorphisms ◽

Mineral Density ◽

Single Nucleotide ◽

Plasma Total Cholesterol Level

Among multiple factors influencing osteoporosis,genetic variations involved in bone-mineralmetabolism can affect risks predisposing to the diseaseonset. Here, we studied single-nucleotide polymorphisms(SNPs) in the pro-opiomelanocortin (POMC)gene for possible association with bone mineral density(BMD) among 384 adult Japanese women and observedsignificant correlation between adjusted BMD and threeSNPs in the promoter region (r>0.14, p<0.01). Themost significant correlation was observed for ?2353G/A(r=?0.16, p=0.002); homozygous carriers of the major(G) allele had the highest BMD (0.405±0.054 g/cm2)while heterozygous carriers were intermediate(0.390±0.053 g/cm2) and homozygous A-allele carriershad the lowest BMDs (0.369±0.048 g/cm2). Althoughno association was detected between these SNPs andbody weight or body mass index (BMI), significantassociation was detected between the ?2313A/C genotypeand plasma total cholesterol level (r=?0.12,p=0.019). We propose that POMC is among the likelysusceptibility genes for osteoporosis and may also beinvolved in dyslipidemia.

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