The Association Between Gene Polymorphisms And Serum Level Of SHBG(Sex Hormone-binding Globulin) And Osteoporosis In Chinese Men

Part One The relationship between sex hormone-binding globulin and bone mineral density and presence of osteoporosis in middle-aged and elderly Chinese males[Objective] This study aims to assess the relationship between SHBG and BMD, bone turnover and presence of osteoporosis among Chinese middle-aged and elderly men.[Methods] A cross-sectional study was carried out among 404 Chinese men, aged over 45 years.BMD was measured with dual-energy x-ray absorptiometry (DXA) and participants’blood was collected for bone alkaline phosphatase(BSAP), SHBG and testosterone(T) assay. Free testosterone (FT) was calculated.[Results] Prevalence of osteoporosis and osteopenia in the study was 26.0% and 54.5%,respectively. Osteoporotic men had lower BMI, free testosterone(FT) and higher levels of SHBG, BSAP than the osteopenia and normal groups. The SHBG level of the osteoporotic group was significantly lower than osteopenia(49.40[41.70,68.50] nmol/L VS 47.35[34.60,59.50] nmol/L, p<0.001) and normal groups (49.40[41.70,68.50] nmol/L VS 42.70[34.25,51.10]nmol/L,p<0.001). When SHBG levels were divided into quartiles, FT levels decreased and prevalence of osteoporosis increased with SHBG levels raised. BSAP level wasn’t significant different among those four groups. Compared with the subjects in the lowest quartile of SHBG level (<36.55nmol/l), subjects in the third quartile(OR[95%CI]=2.998 [1.460-6.157], P=0.002) and the highest quartile(OR[95%CI]=4.439[2.192-8.991], p<0.001) were more likely to suffer with osteoporosis. Spearmen correlation analysis showed that after adjusted for age and BMI, FT was positive related to BMD and SHBG was inversely realted to BMD, while TT was not associated with BMD. No association was found between BSAP and SHBG, TT and FT. Mutiple regression analysis suggested that age, BMI, FT and SHBG were independently associated with BMD. SHBG levels were inversely related to BMD and it could explain 1.4%-2.1% for the variance of BMD, after adjusting for age,BMI, and FT. Logistic regression analysis showed that BMI(95%CI:0.713-0.866,p<0.001), smoking(95%CI:1.141-3.925,p=0.017) and FT(95%CI:0.974-0.998, p=0.020) or SHBG 95%CI:1.006-1.034, p=0.004)was independently associated with the presence of osteoporosis.[Conclusions] Serum FT levels were positive correlated with BMD, while SHBG levels were inversely correlated with BMD. Increasing SHBG levels might be an independent risk factor for osteoporosis among Chinese men.Part two The association between sex hormone binding globulin (SHBG) gene polymorphisms and bone mineral density(BMD) and presence of osteoporosis in middle-aged and elderly Chinese males[Objective] This study aims to investigate the impact of single nucleotide polymorphisms(SNPs) of SHBG gene on SHBG levels, BMD and presence of osteoporosis in Chinese male.[Methods] A group of Chinese men, recruited from a health checkup population at Zhongshan Hospital, Fudan University, aged≥45 years were included in the analysis. Anthropometric measurements were taken, BMD was measured with dual-energy x-ray absorptiometry (DXA) and participants’blood was collected for SHBG and total testosterone(TT) assay.16 SNPs of SHBG gene and the neighboring gene were studied by means of improved multiple ligase detection reaction (iMLDR) assays.[Results] A total of 404 men were included in our study.16SNPs (rs3853894,rs9303218, rs9901675, rs9898876, rs2541012, rs13894, rs858521, rs6259, rs727428, rs1641537, rs1017163, rs11078701, rs858518, rs59524396, rs62059836, and rs8077824) all showed polymorphisms and were all in Hardy-Weinberg equilibrium (p> 0.05). In the single locus analysis, significant associations were found between SHBG levels and four polymorphisms(rs 11078701, rs9901675, rs9898876 and rs2541012) in age-and BMI-adjusted models. In addition, we observed statisticallysignificant differences between osteoporosis patients and control subjects in genotype distributions of rs9898876, rs2541012, rs6259 and rs3853894. Compared with carriers of common genotype, carriers of variant genotype of rs9898876, rs2541012 and rs6259 had lower BMD, while subjects with variant genotype of rs3853894 had higher BMD. In the models with or without adjustment for confounders(age, BMI, SHBG and FT levels), subjects with variant genotype of rs3853894 were less likely to suffer with osteoporosis, compared with subjects with common genotype(OR=0.444,95%CI:0.268-0.736, p=0.002), carriers of variant genotype of rs9898876, rs2541012 and rs6259 were more likely to suffer with osteoporosis than carriers with common genotype, corresponding OR value were 2.445(95%CI:1.497-3.994,p<0.001),2.597(95%CI:1.351-4.992,p=0.004), 2.486(95%CI:1.513-4.083,p<0.001),respectively. In the haplotypes analysis, compared with subjects with the most common haplotype GTG(constituted by the rs9898876[G/T], rs2541012[C/C] and rs6259[G/A]), subjects with TCA haplotype polymorphisms were associatedwith an increased risk of osteoporosis.[Conclusions]Polymorphisms of rs11078701, rs2541012, rs9901675 and rs9898876 were associated with serum SHBG level, polymorphisms of rs3853894, rs9898876, rs2541012, rs6259 were associated with BMD and presence of osteoporosis in Chinese male population.