Osteoporosis: gene interaction between haptoglobin and HFE polymorphisms

Osteoporosis is a common metabolic bone disease characterized by reduced bone mass and increased risk of fragility fractures. The pathogenesis of this disease is complex and influenced by multiple risk factors, where genetic factors play an important role. Osteoporosis and iron metabolism have an important relationship. Iron overload suppresses osteoblast formation and also stimulate osteoclast resorption of bone, suggesting that polymorphisms in genes affecting iron homeostasis can increase the susceptibility for the development of osteoporosis. In the present study, we aimed to analyse the epistatic relationship between two iron metabolism related genes - haptoglobin (Hp) and HFE – in osteoporosis. To achieve this, 313 patients with osteoporosis and 450 controls with normal bone mineral density were enrolled. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis (PAGE) and HFE polymorphisms (H63D and C282Y) were evaluated by PCR-RFLP. All statistical tests were performed with SPSS 24.0 software. Results showed that, no significant differences were found between the two populations (patients vs controls) concerning Hp phenotypes or HFE (H63D and C282Y) genotypes. However, individuals that have co-inherited the Hp 2.2 and the HFE_H63D HH have an increased risk for developing osteoporosis [p=0.049; OR (95% CI) = 2.509 (1.003-6.279)] (adjusted for age and body mass index). In summary, a significant epistatic interaction was detected between haptoglobin and HFE and osteoporosis, where Hp 2.2 in combination with HFE_H63D HH genotype appear to increase the risk for developing osteoporosis. Since these genes are related to iron metabolism, the results of this study reinforce an important action of this metabolism in the development of osteoporosis.