Background: The human homologue of the mouse progressive ankylosis (ANKH) gene is one of the key genetic factors involved in bone mineralization. Previous studies have shown that plasma levels of osteoprotegerin (OPG) and parathyroid hormone (PTH) are associated with the distal region of the ANKH gene, whereas skeletal size measurements are associated with the promoter region.
Aim: The present study examines the possible phenotype-haplotype specificity of the associations in these two gene regions.
Subjects and methods: The total sample consists of 1249 healthy individuals (mean age = 47.7, SD = 16.8) from 404 nuclear families. Fifteen interrelated anthropometric measurements were transformed into two principal components, reflecting body size and mass. Those, plus circulating levels of PTH and OPG, were subjected to association analysis, using transmission disequilibrium tests (TDTs) with ANKH gene. From 805 to 1150 individuals per SNP were genotyped.
Results: In the proximal region (rs3006069-rs835154-rs835141), associations were found between the A-A-C haplotype and the first principal component reflecting body size (p < or = 0.048), whereas another haplotype, G-G-C, was associated with the first principal component, reflecting the body mass (p < or = 0.008). In the distal region of ANKH (rs39968-rs696294-rs875525), the A-A-C haplotype was found to be associated with OPG plasma levels (p < or = 0.001), whereas the G-A-C haplotype was associated with PTH circulating concentrations (p < or = 0.025).
Conclusion: Taken together, the results show discrimination between the corresponding regions and haplotypes, suggesting trait-specific gene variants that influenced bone-related phenotypic variation in the studied population.