Contribution of the putative genetic factors and ANKH gene polymorphisms to variation of circulating calciotropic molecules, PTH and BGP

It is well known that regulation of calcium homeostasis in bone remodeling is one of the most crucial factors for maintaining healthy bones. Parathyroid hormone (PTH) is probably the most important hormone that participates in the bone remodeling process. Another important biochemical factor governing bone metabolism is osteocalcin (BGP). Although the physiological functions of both of these factors are well known, there is still very little known regarding their specific genetic determination and in particular, the specific genes that may regulate the circulating concentrations of these substances. In the present study, we examined whether nine single nucleotide polymorphisms (SNPs) in the human homologue of the mouse progressive ankylosis gene (ANKH) - one of the key genetic factors involved in bone mineralization - can be associated with PTH and BGP levels in apparently healthy human populations. The study sample comprised 244 nuclear families (840 individuals). After adjustment of BGP and PTH for the significant covariates (sex, age and BMI), the contribution of the putative genetic effects was statistically significant (P < 0.001) for both biochemical factors: 45.27 ± 10.8% for PTH and 30.19 ± 12.6% for BGP. Application of transmission disequilibrium tests (TDTs) revealed a significant association (P < 0.05) between PTH and two SNPs: rs39968 and rs875525. However, the association became particularly significant for four TDTs (P-values ranging from 0.0025 to 0.0008) when the association with the haplotypes generated from the above SNP was tested. This association remained significant even after correction for multiple testing with a false discovery rate of 0.05.