CYP19A1 polymorphisms are associated with bone mineral density in Chinese men.

Aromatase-dependent biosynthesis of estrogen plays an important role in maintenance of the male skeleton, and Cytochrome p450 aromatase is the key enzyme to catalyze the conversion of androgen precursors to estrogens. We investigated the association of polymorphisms in the CYP19A1 gene and bone mineral density in a Chinese cohort. 2392 extreme low femoral neck BMD cases or extreme high femoral neck BMD controls were selected from a population-based cohort and genotyped for eight SNPs in the CYP19A1 gene. Significant associations for rs17703883, rs12594287 and rs16964201 SNPs with BMD were found in men only. Men with TC/CC genotypes in the rs17703883 SNP had a 1.5 times higher risk of having extreme low femoral neck BMD (P = 0.003, empirical P value = 0.05), and decreased BMDs at total body (P = 0.004, empirical P value = 0.07) and total hip (P = 0.003, empirical P value = 0.05). Men carrying AA/AG genotypes in the rs12594287 SNP had a 30% reduced risk of having extreme low femoral neck BMD (P = 0.007, empirical P value = 0.12), and increased BMDs at total body (P = 0.0009, empirical P value = 0.018) and total hip (P = 0.001, empirical P value = 0.02). Men carrying TT/TC genotypes in the rs16964201 SNP had a 40% reduced risk of having extreme low femoral neck BMD (P = 0.005, empirical P value = 0.087), and increased BMDs at total body (P = 0.0001, empirical P value = 0.002) and total hip (P = 0.0006, empirical P value = 0.012). Haplotype analysis showed that the G-C-T-A-T haplotype was significantly related to higher BMD. Our finding suggests that genetic variations in the CYP19A1 gene are significantly associated with BMD at different skeletal sites in adult men, but not in women.

Large-scale genome-wide linkage analysis for loci linked to BMD at different skeletal sites in extreme selected sibships.

UNLABELLED: Few genome-wide linkage studies of osteoporosis have been conducted in the Asian population. We performed a genome-wide scan involving 3093 adult siblings with at least one sib-pair extremely concordant or discordant for hip BMD. Our results indicated four genome-wide significant QTLs for BMD. In comparison with 12 previous reported linkage studies, we reveal novel linkage regions that have reaching global significance. INTRODUCTION: The genetic basis for osteoporosis has been firmly established, but efforts to identify genes associated with this complex trait have been incomplete, especially in Asian populations. The purpose of this study was to identify quantitative trait loci (QTLs) for BMD in a Chinese population. MATERIALS AND METHODS: We performed a genome-wide scan involving 3093 siblings 25-64 years of age from 941 families, with at least one sib-pair extreme concordant or discordant for total hip BMD from a large community-based cohort (n = 23,327) in Anhui, China. Linkage analysis was performed on BMD residuals adjusted for age, height, weight, occupation, cigarette smoking, physical activity, and alcohol consumption using the revised Haseman-Elston regression-based linkage model. RESULTS: Our results revealed significant QTLs on chromosome 7p21.2 for femoral neck BMD (LOD = 3.68) and on chromosome 2q24.3 for total hip BMD (LOD = 3.65). Suggestive linkage regions were found to overlap among different skeletal sites on chromosomes 2q, 7p, and 16q. Sex-specific linkage analysis further revealed a significant QTL for lumbar spine BMD on chromosome 13q21.1 (LOD = 3.62) in women only. When performing multivariate linkage analysis by combining BMDs at four skeletal sites (i.e., whole body, total hip, femoral neck, and lumbar spine BMD), an additional significant QTL was found at chromosome 5q21.2 (LOD = 4.56). None of these significant QTLs found in our study overlapped with major QTLs reported by other studies. CONCLUSIONS: This study reveals four novel QTLs in a Chinese population and suggests that BMD at different skeletal sites may also share common genetic determinants.

Impact of seafood and fruit consumption on bone mineral density.

OBJECTIVES: Over the past decade, dietary choices and nutrition have proven to be major modulators of bone mineral density (BMD) in men and women. We investigated environmental determinants, specifically dietary habits, of BMD by using multiple regression models in a rural Chinese population. METHODS: BMDs were measured at the hip and total body in 5848 men and 6207 women, aged 25-64. Dietary and supplemental intakes were assessed by a simple, one-page questionnaire tailored to collect nutritional information from large rural populations. Another questionnaire was used to collect information on the subjects' age, disease history, smoking, alcohol consumption, physical activity as well as women's menstrual status and reproductive history. Multiple regression models were used to assess the relationships among dietary variables and BMD, after adjusting for age, BMI (body mass index), weight, occupation, smoking status, and alcohol consumption. RESULTS: Increasing seafood consumption was significantly associated with greater BMD in women (p<0.001), especially those consuming more than 250 g per week of seafood. One thousand and three hundred and twenty-four men and 1479 women consumed >250 g of fruit per week. Higher fruit intake was found to be significantly associated with higher BMD in both sexes (p<0.05). High vegetable consumption, however, did not positively impact BMD. CONCLUSIONS: This study with its large population size has identified preventive measures, as well as some risk factors, involved in bone loss and osteoporosis. Our results highlight the importance of several dietary variables as significant determinants of BMD. It also emphasizes the role of dietary intake in general and shows that specific foods, such as fruits and seafood, can positively impact BMD.

Association of the methylenetetrahydrofolate reductase C677T polymorphism and fracture risk in Chinese postmenopausal women.

Osteoporotic fractures are a leading cause of disability and, indirectly, of death in the elderly population. Previous studies have shown that homocysteine level and the C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) may be involved in the development of osteoporosis and its related fracture in European populations. The aim of this study was to verify the association of this polymorphism with bone mineral density (BMD) and fractures in our 1899 Chinese postmenopausal women. The C677T T allele frequency in this population was 39.2%. The distribution of the MTHFR genotypes followed the Hardy-Weinberg equilibrium. BMD at total body, total hip or femoral neck did not significantly vary with MTHFR C677T genotype. The T allele carrier tended to have higher risk of having osteoporosis or osteopenia, but the difference was statistically insignificant. However, Poisson regression analysis revealed that the T allele carriers had an increased risk of fractures (RR=1.7, 95% CI=1.1-2.7, p=0.01) which occurred before or after menopause. As far as fracture incidence after menopause was concerned, the CT or TT genotype had more than twice the risk of the CC genotype (RR=2.5, 95% CI=1.2-4.9, p=0.009). This association was independent of age, physical activity, occupation, passive smoking, height, weight, years since menopause, and total hip BMD. Our data show that the MTHFR C677T polymorphism is an independent predictor of fracture risk, although it only had a weak effect on BMD. Further study on the mechanistic role that this polymorphism plays in the development of fractures may lead to better understanding of the etiology of osteoporotic fracture.

Prevalence and physical determinants of low back pain in a rural Chinese population.

STUDY DESIGN: This was a community-based cross-sectional study that is part of an ongoing study of genetics and osteoporosis. OBJECTIVES: To estimate the 1-year self-reported prevalence of low back pain (LBP); and to assess the association between physical exposures (occupation, physical stress, and vibration) and LBP in a rural Chinese population. This study also explored how these associations change when individuals with LBP report additional pains in other parts of the body. SUMMARY OF BACKGROUND DATA: Little is known about the prevalence and determinants of LBP in rural developing populations, even though approximately half of the world's population, mostly from the developing world, is engaged in agriculture, a known strenuous activity. METHODS: Families with at least three participating siblings residing in the surrounding rural region of Anqing city, Anhui Province, China, were invited to participate in the study through public announcements and direct invitations by village physicians. A questionnaire including demographics, physical exposures, and musculoskeletal pain was administered to 13,965 men and women (age, 25-64 years). Generalized estimating equations were used to estimate LBP prevalence and examine associations between LBP and physical exposures. RESULTS: The 1-year prevalence of LBP was 64%. Twenty-five percent reported no pain at any body site. Women had higher prevalence of LBP than men across all age groups. Being a farmer, reporting moderate or heavy physical stress, and having had former or current exposures to vibration were positively associated with LBP (P < 0.05). Physical exposures were also associated with cases of LBP combined with other musculoskeletal pains, and generally, the more pains individuals reported, the more likely it was that they were farmers and were exposed to vibration. CONCLUSION: A high prevalence of LBP and LBP with additional musculoskeletal pain existed in this rural Chinese sample. We found evidence of a link between physical exposures and LBP, and LBP with additional musculoskeletal pain. Further understanding of the characteristics and risk factors of LBP in rural developing areas is needed.

Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women.

BACKGROUND: Higher fat mass may be an independent risk factor for osteoporosis and osteoporotic fractures. OBJECTIVE: We aimed to determine the independent contribution of fat mass to osteoporosis and to estimate the risk of osteoporotic fractures in relation to body weight, lean mass, and other confounders. DESIGN: This was a community-based, cross-sectional study of 7137 men, 4585 premenopausal women, and 2248 postmenopausal women aged 25-64 y. Total-body and hip bone mineral content (BMC) and bone mineral density (BMD) and body composition were measured by dual-energy X-ray absorptiometry. Serum lipids were measured. Sex- and menopause-specific multiple generalized linear models were applied. RESULTS: Across 5-kg strata of body weight, fat mass was significantly inversely associated with BMC in the whole body and total hip. When we compared the highest quartile with the lowest quartile of percentage fat mass in men, premenopausal women, and postmenopausal women, the adjusted odds ratios (95% CIs) of osteoporosis defined by hip BMD were 5.2 (2.1, 13.2), 5.0 (1.7, 15.1), and 6.9 (4.3, 11.2), respectively. Significant linear trends existed for higher risks of osteoporosis, osteopenia, and nonspine fractures with higher percentage fat mass. Significant negative relations were found between whole-body BMC and cholesterol, triacylglycerol, LDL, and the ratio of HDL to LDL in all groups. CONCLUSIONS: Risks of osteoporosis, osteopenia, and nonspine fractures were significantly higher for subjects with higher percentage body fat independent of body weight, physical activity, and age. Thus, fat mass has a negative effect on bone mass in contrast with the positive effect of weight-bearing itself.

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men.

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5' UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P = 0.004), and lower whole body BMD (P < 0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P < 0.01), and higher whole body BMD (P < 0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P < 0.05), and higher whole body BMD (P < 0.01). Significant gene-gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.

Familial aggregation of bone mineral density and bone mineral content in a Chinese population.

Familial aggregation of bone mineral density (BMD) and bone mineral content (BMC) has been shown in twin and familial studies, but most sample sizes were small. We here report a large familial aggregation study in a Chinese population. A total of 13,973 siblings aged 25-64 years from 3,882 families were enrolled from Anhui, China. We assessed the whole-body, hip and lumbar spine BMD and BMC by dual-energy X-ray absorptiometry (DXA). Intra-class correlation coefficients of BMD and BMC between siblings varied among different skeletal sites and between different age groups of male sib-pairs and premenopausal and postmenopausal female sib-pairs, with a range of 0.228 to 0.397. The sibling recurrence risk ratio (lambdas) of osteoporosis was 2.6 in our population. We also evaluated the joint association of the BMD values of the first siblings and the second siblings with the risk of low BMD (defined as less than the 10th percentile of the same group population) of their younger siblings. If both the first and second siblings' BMDs were in the lowest tertile, the odd ratios (ORs) of low BMD in their subsequent siblings were 8.32 [95% confidence interval (CI) 5.59-12.39)], 8.71 (95% CI 5.74-13.22) and 5.90 (95% CI 3.57-9.76) for total body, total hip and lumbar spine, respectively. This study demonstrates a significant familial aggregation of BMD and BMC in a large sample of rural Chinese adults.

Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene.

Type 1 diabetes (T1D) is a complex autoimmune disease. Several genetic loci have been implicated in the susceptibility to this illness. Evaluated was the role of the CTLA4 exon 1 A49G polymorphism and its role as a risk factor for T1D in our population. DNA from 190 patients with T1D and their families and 96 control individuals were genotyped for CTLA4 exon 1 polymorphism and human leukocyte antigen (HLA)-DQB1*0201 and *0302 haplotypes by polymerase chain reaction (PCR) amplification-restriction enzyme analysis and PCR amplification that used sequence-specific primers, respectively. Patients were nonobese and <26 years old. The CTLA4 G allele was found to be more frequently present in patients with T1D (32.4%) as compared with its frequency in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). chi(2) analysis and family-based association studies were performed and suggested the association of CTLA4 exon 1 G polymorphism with T1D (p = 0.0229). Furthermore, in HLA-DQB1*0201-positive patients with T1D, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. This study suggests that CTLA4 is a candidate susceptibility gene for T1D.

No association between the -1031 polymorphism in the TNF-alpha promoter region and type 1 diabetes.

Tumor necrosis factor alpha (TNF-alpha) is an important immunomodulator and is believed to be involved in the development or progression of type 1 diabetes. In the following study, we evaluated TNF-alpha promoter polymorphisms at positions -863 and -1031 and their association with type 1 diabetes in a group of 210 diabetic patients from Lebanon. Our results show that in our population, the C allele is predominant at position -863, whereas the A allele is very rare (2%). At position -1031, however, the C and T allele distribution was similar in both the patient (17.8% vs 82.2%, respectively) and the control (21.4% vs 79.6%) groups. No association of TNF-alpha genotype at position 1031 with type 1 diabetes was found as demonstrated by the family-based association test and the transmission disequilibrium test. However, when patient genotypes were compared, the recessive CC genotype was only found in type 1 diabetic males but not in type 1 diabetic females. This observation, however, requires further investigation in a larger sample before conclusive association to gender is suggested. In conclusion, our results demonstrate that no association between TNF-alpha polymorphism and type 1 diabetes seems to exist in our population.

[A linkage disequilibrium study of methylenetetrahydrofolate reductase C677T and schizophrenia].

OBJECTIVE: To explore the relationship between the methylenetetrahy drofolate reductase (MTHFR) C677T missense mutation and schizophrenia by linkage disequilibrium study. METHODS: Linkage disequilibrium analys is was conducted bet ween MTHFR C677T and schizophrenia in 115 affected-sib-pair (105) and trios (10) families by XDT and MAPMAKER/SIBS soft system. The analyses were performed in different diagnostic categories and combined with the age of onset as well. RESULTS: No positive results were found in the analysis in all the family in all the four diagnostic categories. Significant P values, which were P<0.05, P<0.01 respectively, were observed in the families with the affected individual's onset age less than 25 years in all the four diagnostic categories. CONCLUSION: The missense mutation of MTHFR C677T or other gene structure around this mutation may be one of the susceptibility gene of schizophrenia.

[Linkage disequilibrium study of microsatellite markers on chromosome 6 and schizophrenia].

OBJECTIVE: To explore the relationship between the microsatellite markers on chromosome 6 and schizophrenia by linkage disequilibrium analysis. METHODS: Twenty-eight microsatellite markers on chromosome 6 were evaluated in 115 affected-sib-pair and trios families. Linkage disequilibrium analysis was conducted according to diagnostic categories, Positive and Negative Syndrome Scale (PANSS) and other clinical data by XDT and MAPMAKER/SIBS software system. RESULTS: Significant P value (P<0.005) was found in all the four diagnostic categories. Only the locus of D6S1960 showed positive P value (P<0.05) in all the subgroups divided by PANSS scale and the age of onset. CONCLUSION: The area around D6S1960 in short arm of chromosome 6 may contain susceptibility gene of schizophrenia.