A Role Of Pleotropic Rankl Gene Underlying Covariation Of Compressive Strength Index And Body Mass Index

Osteoporosis (OP) is a systemic skeletal disorder characterized by low bone mass and micro-architectural deterioration in bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis fractures, mainly occurred in elderly people, are an important cause of mortality and morbidity. Bone mineral density (BMD) was usually used to predict the risk of osteoporotic fracture and was an important determinant of bone strength, but BMD could only explain50%—70%of total bone strength. Other variables were used to predict the risk of osteoporotic fracture. Compression strength index (CSI) of femoral neck (FN) is a newly developed parameter to improve the performance of risk assessment of hip fractures and it assemble many variables such as BMD,bone geometry、weight. And earlier studies suggested that CSI are highly genetically correlated with body mass index (BMI). However, the shared SNPs/genes between them are largely unknown. At present, the most popular method for identifying genetic factors is univariate genome wide association study (GWAS). However, univariate analysis ignores the pleiotropic effect of genes which play important roles in multiple disease pathogenesis. To identify the specific SNPs/genes shared between CSI and BMI, we performed a bivariate genome-wide association study (GWAS) in a large sample of Chinese population.A total of1,627unrelated Han Chinese adults (802males and825females) were recruited for this bivariate GWAS. The CSI are calculated based on the BMD and bone size at the femoral neck (FN). Bone mineral density (BMD) and bone size at the FN and BMI were measured by dual-energy X-ray absorptiometry (DXA). About900,000eligible SNPs were genotyped by using Affymetrix GeneChip Human Mapping SNP6.0arrays, and689,368SNPs were selected for the subsequent association analyses. We conducted the bivariate GWAS for CSI and BMI using R software based on a linear model to detect association between a SNP and two phenotypes. A total of81SNPs were associated with the phenotype pair of CSI and BMI reached the bivariate p value level of p<1×10-4.The top16SNPs showing the most significant signal are rs927623, rs2388001,rs17536071, rs12868231, rs17536002, rs1324005, rs9315919, rsl6881912, rs12864265, rs9590697, rs912423, rs377046, rs3862738, rs7316953, rs720824,rs7633246, with p values ranging from2.42×10-6to9.63×10-6. Among them, two SNPs located at SEMA5A and one SNP located at downstream of PEX2. Interestingly, a group of12contiguous SNPs are locating in a haplotype block, which spans a region of~90kb located at~50kb upstream of TNFSF11.We replicated the top16SNPs in2286unrelated Caucasians and found10significant associated SNPs with p value less than0.05, rs927623, rs17536071, rs12868231, rs17536002, rs1324005, rs9590697, rs912423, rs3862738, rs7316953, rs720824, their p values rang from0.007to0.05in the Caucasian sample. Meta-analyses yielded corresponding combined p values is1.49X10-6,2.57×10-6,2.04×10-6,1.71×10-6,2.64X10-6,3.60×10-6,2.93×10-6,5.59×10-6,4.28X10-6,1.12×10-6, respectively. These10SNPs are located in a LD block at13q14.11, which located at the upstream of the tumor necrosis factor (ligand) superfamily, member11(TNFSF11) gene. Previous studies suggested that the TNFSF11gene was functionally related to osteoporosis, bone metabolism and osteoclast differentiation and also related to obesity, fat metabolism, weight. This was the first study suggested that the TNFSF11gene maybe a pleiotropic gene underlying covariation for both CSI and BMI.