Dataset Information

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.

SUBMITTER: Jin HS

PROVIDER: S-EPMC4530967 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women.

Jin Hyun-Seok HS Kim Jeonghyun J Park Sangwook S Park Eunkuk E Kim Bo-Young BY Choi Vit-Na VN Yoo Young-Hyun YH Kim Bom-Taeck BT Jeong Seon-Yong SY

PloS one 20150810 8

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 fur ...[more]

PMID: 26258864

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Project description:Vitamin D receptor (VDR) is one of the main mediators of vitamin D biological activity. VDR dysfunction might substantially contribute to development of postmenopausal osteoporosis (PMO). Numerous studies have revealed the effects of several VDR gene variants on osteoporosis risk, although significant variation in different ethnicities have been suggested. The main purpose of this work was to assess the frequency of distribution of VDR genetic variants with established effect and evaluate their haplotype association with the risk of PMO in a cohort of Belarusian and Lithuanian women. Case group included women with PMO (n?=?149), the control group comprised women with normal bone mineral density (BMD) and without previous fragility fractures (n?=?172). Both groups were matched for age, height, sex, and BMI-no statistically significant differences observed. VDR gene polymorphic variants (ApaI rs7975232, BsmI rs1544410, TaqI rs731236, and Cdx2 rs11568820) were determined using polymerase chain reaction and restriction fragment length polymorphism. The lumbar spine (L1-L4) and femoral neck BMD was measured using dual-energy X-ray absorptiometry. Association between each VDR variant and PMO risk was assessed using multiple logistic regression. The genotyping revealed statistically significant difference in the rs7975232 genotype frequencies between the patients and the controls (homozygous C/C genotype was overrepresented in patients, p?=?0.008). Patients with osteoporosis were also three times more likely to carry the rs1544410 G/G genotype, when compared to controls. We found that rs7975232, rs1544410, and rs731236 variants were in a strong direct linkage disequilibrium (p?<?0.0001), suggesting that risk alleles of these markers are preferably inherited jointly. For the bearers of C-G-C haplotype (consisting of rs7975232, rs1544410, and rs731236 unfavorable alleles), the risk of PMO was significantly higher (OR?=?4.7, 95% CI 2.8-8.1, p?<?0.0001) compared to controls. This haplotype was significantly over-represented in PMO group compared to all other haplotypes. Our findings highlight the importance of identified haplotypes of VDR gene variants. Complex screening of these genetic markers can be used to implement personalized clinical approach for prevention, treatment, and rehabilitation programs.

Project description:Osteoporosis is a polygenic disorder and has been demonstrated to be associated with ~30 candidate genes, the majority of which have also been implicated in the regulation of bone mineral density (BMD). Vitamin D receptor (VDR) is the candidate gene that has been most extensively studied. Certain studies have reported that the VDR single nucleotide polymorphism ApaI is associated with the risk of osteoporosis in Caucasian and African women. However, this association has not yet been studied in postmenopausal Han Chinese women in the Xinjiang area. In the present study, ApaI polymorphisms of VDR were defined by polymerase chain reaction-restriction fragment length polymorphism, in order to analyze the distribution of ApaI polymorphisms in postmenopausal Han Chinese women from Xinjiang. BMD was measured by dual energy X-ray absorptiometry at the lumbar spine (L2-4), Ward's triangle, great trochanter and femoral shaft. A total of 336 women were included in this study. The genotype distribution of ApaI was consistent with the Hardy-Weinberg equilibrium (all P>0.05). There were no significant differences in ApaI genotype frequencies between the 90 cases in the osteoporosis group and 246 cases in the non-osteoporosis group (P=0.946). Meanwhile, it was identified that BMD values of the tested locations were negatively correlated with age (P<0.05) and positively correlated with body mass index (BMI; P<0.05). On further attribution risk analysis, BMD was identified as a risk factor [odds ratio (OR): 0.464, 95% confidence interval (CI): 0.372-0.580, P=0.001] and BMI a protective factor (OR: 1.502, 95% CI: 1.008-2.240, P=0.032) in osteoporosis. When BMD was adjusted for confounding factors including age and BMI, it was observed that the ApaI polymorphism was not associated with BMD at the sites tested (P>0.05). In conclusion, the present study identified no significant association of the common VDR polymorphism ApaI with BMD at several skeletal sites in postmenopausal Han Chinese women in the Xinjiang area. Age was negatively correlated with BMD at different sites and identified as a risk factor; while BMI was positively correlated with BMD and identified as a protective factor.

Project description:The correlation of genetic polymorphisms of GALNT3 and vitamin D receptor (VDR) with osteoporosis in postmenopausal women was investigated. A total of 1,212 cases of postmenopausal patients diagnosed with osteoporosis (observation group) and 404 cases of postmenopausal women without osteoporosis (control group) were selected. Dual-energy X-ray absorptiometry was used for measurement of bone mineral density (BMD) of lumbar vertebrae L2-4, proximal femoral neck and total hip, and classifications were made. TaqMan genotyping technology was employed to examine tag single-nucleotide polymorphism (tagSNP) of GALNT3 and VDR and the correlation of tagSNP with bone turnover markers (BTMs) and serum calcium and phosphorous levels was analyzed. The multiple logistic regression analysis was used to screen risk factors for osteoporosis. A comparison of age and menopause time of the two groups, yielded no statistical significance difference (P>0.05). BMD and T values of the lumbar vertebrae, femoral neck and total hip in the observation group were significantly lower than those in the control group, and the differences were statistically significant (P<0.05). A comparison of the degree of osteoporosis, yielded statistically significant differences (P<0.05). The proportion of tagSNP of 5 loci in GALNT3 and 3 loci in VDR in the observation group was significantly higher than that in the control group, and the differences were of statistical significance (P<0.05). Levels of 25-OHD3, ?-CTX, P1NP and serum calcium in the observation group were lower than those in the control group and the level of serum phosphorus in the observation group was higher than that in the control group, and all of these results were statistically significant (P<0.05). The result of the correlation analysis revealed that rs1425000 and rs757343 were negatively correlated with BTM and serum calcium and phosphorus levels (P<0.05). The result of the regression analysis revealed that 8 tagSNPs were independent risk factors for osteoporosis. Genetic polymorphisms of GALNT3 and VDR were closely associated with osteoporosis in postmenopausal women.

Dataset Information

Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women.

Publications

Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women.

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