Association Between SNP And Haplotypes In METTL21C Gene And Peak Bone Mineral Density And Body Composition In Chinese Male Nuclear Families

Objective: Bone mineral density(BMD) and body composition are intricate traits, there are intrinsic inter connections between them. Recent studies have shown that The methyltransferase-like 21C(METTL21C), known as C13orf39, located on 13q33.1, has 264 amino acid and as a member of seven-β-strand methyltransferase superfamily could catalyze the transfer of a methyl group(CH3) from a donor to the acceptor of the 70-k Da heat shock protein(Hsp70). METTL21 C gene, which mainly expressed in muscle, could promote the differentiation of myoblasts to myotubes through modulate the NF-κB signaling pathway and regulate the intracellular homeostasis of calcium in muscle, as well as reduced the glucocorticoid-induced apoptosis in osteocyte. Therefore, the aim of our study was to explore the association between the single nucleotide polymorphisms(SNPs) and haplotypes of METTL21 C gene with peak bone mineral density(BMD) and body composition in Chinese male nuclear families.Methods: We recruited 400 Chinese male-offspring nuclear families with 1215 individuals comprising 800 parents and 415 healthy sons aged 20 to 40 years-old. Fifteen tagging SNPs(rs641652, rs660207, rs9585961, rs7988265, rs896000, rs595825, rs9518810, rs7984675, rs654454, rs3858792, rs9514044, rs7981120, rs2390760, rs966724 and rs599976) in METTL21 C gene were selected using the Hap Map databases and Haploview software, which identifies the linkage disequilibrium(LD) of r2>0.8 and the minor allele frequency(MAF) at least 0.05. After that, SNPs were genotyped by the 3730 XL genetic analyze sequenator using im LDR Multiplex kit. The peak BMD in lumbar spine, femur neck and total hip, the body composition comprised of total fat mass(TFM) and total lean mass(TLM) were measured by dual-energy X-ray absorptiometry(DXA). The association analyses were performed using the SPSS software and the quantitative transmission disequilibrium test(QTDT).Results: For ANCOVA tests, both rs9518810 and rs7984675 were associated with femoral neck BMD and total hip BMD(p = 0.005, 0.032, 0.035 and 0.035, respectively); rs7988265, rs2390760 and rs599976 were associated with BMI(p = 0.023, 0.005 and 0.023, respectively); rs595825 and rs654454 were associated with TLM(p = 0.043, 0.045, respectively). Significant within-family association analyses with polymorphisms were found between rs9585961 with lumbar spine BMD and femoral neck BMD(p = 0.035, 0.015, respectively); rs9518810 with femoral neck BMD(p = 0.028); rs660207 with TFM(p = 0.024); rs7981120 with BMI(p = 0.042); rs599976 with BMI and TFM(p = 0.012, 0.022, respectively). Only rs9585961 were associated with femoral neck BMD and total hip BMD(p = 0.024, 0.043, respectively); rs9518810 were associated with femoral neck BMD(p = 0.029); rs599976 were associated with BMI, TFM and TLM(p = 0.025, 0.04 and 0.044, respectively)after 1000 permutations of within-family association of QTDT. Meanwhile, the association analyses with haplotypes shown that both the AG and GA haplotypes in block1 were significantly associated with TFM(p = 0.009, 0.047 respectively), and haplotype CAG in block2 was associated with the lumbar spine BMD(p = 0.031).Conclusions: Our study, for the first time, manifested that the polymorphisms and haplotypes of METTL21 C contribute to the peak BMD and body composition in Chinese males. Our study found significant associations between rs660207, rs7981120 and rs599976 with BMI and TFM; while rs9585961 and rs9518810 has significant associations with BMD, which suggests that it may has potential influence on peak BMD and body composition.