| Background:Osteoporosis is a major public health problem worldwide, caused by both environmental and genetic factors. It is mainly characterized by low bone mineral density (BMD) and/or low-trauma osteoporotic fractures (OF). Previous epidemiological studies reported the individual's living environment and health behavior were correlated with the disease. The two important phenotypes were under strong genetic control. However, few previous reprots were revealed on osteoporosis related health belief, behavior and envrionmental factors in Chinese community population. The genetic loci and mechanism of BMD and OF were unclear.Objective:1. To understand the environmental factors, health behavior and health belief correlated with osteoporosis, in a community-based population, and to analyze the effect factors on BMD;2. To verify the potential associations between BMD and candidate genes/loci reported by GWAS of FHS100K, Icelandic deCODE and UK-NL;3. To explore the effect and mechanism of TRAIL pathway on Chinese osteoporostic hip fracture population.Methods:1. Epidemiological investigationDescriptive epidemiological method was applied. Xi'an city from Shaanxi province, Jiayuguan city from Gansu province and the peripheral area of the cities were selected by a convinient sampling. A stratified sampling was then used to select the 700 individuals from 4 resident community of 2 towns in Jiayuguan city and 8 resident community of 4 administrative district in Xi'an city. Face to face interview was applied in the osteoporosis environmental factors, related behavior and health belief investigation. BMD measurements with Dual energy X-ray absorptiometry (DXA) from 100 individuals were used to evaluate bone health status at hip. BMD related factors were analyzed.2. Candidate genes/loci association analysisBy using genotypic information from our Affymetrix 500K SNP arrays and association analytical method, we tested the associations between BMD and 139 SNPs, which were reveaveled from three very recent genome-wide association studies (GWASs), in 1,000 unrelated US whites. Fisher's combined probability method was used to quantify the overall evidence of association.3. Effect of TRAIL pathway on osteoporostic hip fractureA case-control mehod was applied. By using a pathway-based analysis, the effect of TRAIL pathway on Chinese osteoporostic hip fracture was examined. The key genes/loci in TRAIL pathway were explored.4. Statistical analysisStudent-t test, ANOVA, and Logistic regression were used to analyze the osteoporosis epidemiological data; Candidate genes/loci association and the overall effect were analyzed by using IMPUTE,SNPTEST and Fisher's combined probability method; PERMUTATION and PLINK software were used to estimate the genetic pathway on osteoporostic hip fracture.Results:1. The community population above 40 years old was lack of the perception of osteoporosis seriousness. The health motivation should be improved. They intook less milk and soybean. Although the majority population exercise, but the duration and intention were not enough.2. 38 SNPs associated with BMD were successfully replicated (P < 0.05)from 139 SNPs revealed by three recent GWASs, in 1,000 unrelated US whites. Among them, 10 SNPs associated with BMD in specific site and gender achieved significant combined P values < 3.6×10-4 (0.05 / 139 SNPs, corrected for multiple-testing).3. TRAIL pathway had significant effect(P = 0.01)on osteoporostic hip fracture. In TRAIL pathway, the significant loci covering 7 important genes. Statistical importance denoted by the most important SNP for each gene was as following: TNFSF10(TRAIL, P = 1.70×10-4),CFLAR(FLIP, P=3.17×10-3),TNFSF11(RANKL, OPGL, P = 6.06×10-3),TNFRSF11A (RANK, P = 7.63×10-3),TNFRSF10B(TRAILR2, P = 1.07×10-2),TRAF3(P = 1.67×10-2),NFKB1(P = 2.04×10-2)。 Conclusion:1. The osteoporosis health belief and the related health behavior in the community population should be improved.2. Osteoporosis susceptibility of 38 SNPs was verified in 1,000 unrelated US whites. The overall associtions between specific BMD and 10 SNPs were realved even after strict multiple correction.3. TRAIL pathway was important in the osteoporostic hip fracture. The key genes/loci may effect greatly in the etiology of osteoporostic hip fracture.
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