Abstract
To identify novel susceptibility variants for osteoporosis in Korean postmenopausal women, we performed a genome-wide association analysis of 1180 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 405 individuals with osteoporosis and 722 normal controls of the Korean Association Resource cohort. A logistic regression analysis revealed 72 nsSNPs that showed a significant association with osteoporosis (p<0.05). The top 10 nsSNPs showing the lowest p-values (p = 5.2×10-4–8.5×10-3) were further studied to investigate their effects at the protein level. Based on the results of an in silico prediction of the protein’s functional effect based on amino acid alterations and a sequence conservation evaluation of the amino acid residues at the positions of the nsSNPs among orthologues, we selected one nsSNP in the SQRDL gene (rs1044032, SQRDL I264T) as a meaningful genetic variant associated with postmenopausal osteoporosis. To assess whether the SQRDL I264T variant played a functional role in the pathogenesis of osteoporosis, we examined the in vitro effect of the nsSNP on bone remodeling. Overexpression of the SQRDL I264T variant in the preosteoblast MC3T3-E1 cells significantly increased alkaline phosphatase activity, mineralization, and the mRNA expression of osteoblastogenesis markers, Runx2, Sp7, and Bglap genes, whereas the SQRDL wild type had no effect or a negative effect on osteoblast differentiation. Overexpression of the SQRDL I264T variant did not affect osteoclast differentiation of the primary-cultured monocytes. The known effects of hydrogen sulfide (H2S) on bone remodeling may explain the findings of the current study, which demonstrated the functional role of the H2S-catalyzing enzyme SQRDL I264T variant in osteoblast differentiation. In conclusion, the results of the statistical and experimental analyses indicate that the SQRDL I264T nsSNP may be a significant susceptibility variant for osteoporosis in Korean postmenopausal women that is involved in osteoblast differentiation.
Highlights
Osteoporosis is a common skeletal disease characterized by a decreased bone mass, resulting in an enhanced risk of bone fracture [1, 2]
We found 72 nonsynonymous single nucleotide polymorphisms (nsSNPs) that showed a significant association with osteoporosis (p
NsSNPs conferring amino acid changes are advantageous because they permit experimental validation of the statistically identified genetic variants
Summary
Osteoporosis is a common skeletal disease characterized by a decreased bone mass, resulting in an enhanced risk of bone fracture [1, 2]. In the past two decades, robust candidate-gene approach association studies, genome-wide association (GWA) studies, and meta-analyses have been conducted to identify the genetic variations that are associated with bone mass, BMD, osteoporosis, and/or osteoporotic fracture. These studies have uncovered numerous putative single-nucleotide polymorphisms (SNPs) in many genes/loci [7, 11,12,13,14]. At this time, there are 988 genes listed in the HuGe Navigator database (http://hugenavigator.net) associated with osteoporosis. Considering the high heritability (h2, 25–85%) of osteoporosis-related phenotypes, including BMD and fracture [8], the vast majority of genes/loci of susceptibility for osteoporosis and/or osteoporosis-related traits remain to be identified
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