title: Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women.
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.
authors.affiliation: Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University, Asan, Republic of Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Jin
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Laboratory Science, College of Health, Kyungwoon University, Gumi, Republic of Korea.
authors.forename: Sangwook
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Eunkuk
authors.initials: E
authors.lastname: Park
authors.affiliation: Division of Intractable Disease, Center for Biomedical Sciences, National Institute of Health, Korea Centers for Disease Control & Prevention, Cheongju, Republic of Korea.
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Vit-Na
authors.initials: VN
authors.lastname: Choi
authors.affiliation: Department of Anatomy and Cell Biology and Mitochondria Hub Regulation Center, College of Medicine, Dong-A University, Busan, Republic of Korea.
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: Yoo
authors.affiliation: Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Bom-Taeck
authors.initials: BT
authors.lastname: Kim
authors.affiliation: Department of Medical Genetics, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea.
authors.forename: Seon-Yong
authors.initials: SY
authors.lastname: Jeong
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density; D002113:Calcification, Physiologic; D016022:Case-Control Studies; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology; D016015:Logistic Models; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015663:Osteoporosis, Postmenopausal / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011808:Quinone Reductases / Q000235:genetics* / Q000378:metabolism; D056910:Republic of Korea / Q000453:epidemiology; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D011808:Quinone Reductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C000629228:SQOR protein, human; D000469:Alkaline Phosphatase; D006862:Hydrogen Sulfide