RRC ID 45478
Author Jin HS, Kim J, Park S, Park E, Kim BY, Choi VN, Yoo YH, Kim BT, Jeong SY.
Title Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women.
Journal PLoS One
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.
Volume 10(8)
Pages e0135285
Published 2015-1-1
DOI 10.1371/journal.pone.0135285
PII PONE-D-15-20023
PMID 26258864
PMC PMC4530967
MeSH Aged Alkaline Phosphatase / genetics Alkaline Phosphatase / metabolism Biomarkers / metabolism Bone Density Calcification, Physiologic Case-Control Studies Cell Differentiation Core Binding Factor Alpha 1 Subunit / genetics Core Binding Factor Alpha 1 Subunit / metabolism Female Gene Expression Genome-Wide Association Study Genotype Humans Hydrogen Sulfide / pharmacology Logistic Models Middle Aged Monocytes / metabolism Monocytes / pathology Osteoblasts / drug effects Osteoblasts / metabolism* Osteoblasts / pathology Osteoclasts / drug effects Osteoclasts / metabolism Osteoclasts / pathology Osteoporosis, Postmenopausal / epidemiology Osteoporosis, Postmenopausal / genetics* Osteoporosis, Postmenopausal / metabolism Osteoporosis, Postmenopausal / pathology Oxidoreductases Acting on Sulfur Group Donors / genetics* Oxidoreductases Acting on Sulfur Group Donors / metabolism Polymorphism, Single Nucleotide* Postmenopause / genetics* Postmenopause / metabolism Primary Cell Culture Quinone Reductases / genetics* Quinone Reductases / metabolism Republic of Korea / epidemiology Sp7 Transcription Factor Transcription Factors / genetics Transcription Factors / metabolism
IF 2.74
Times Cited 5
Human and Animal Cells MC3T3-E1(RCB1126)