Vitamin K epoxide reductase (VKORC1) gene mutations in osteoporosis: A pilot study

Susceptibility to osteoporosis seems to be influenced genetically. Previous studies on the effects of genetic polymorphisms on bone mineral density (BMD) showed controversial results. Vitamin K hydrochinon is an important cofactor for gamma carboxylation of osteocalcin. The reduction of vitamin K to vitamin K hydrochinon depends on the vitamin K epoxide reductase complex subunit 1 (VKORC1). We evaluated the impact of polymorphisms in VKORC1 on BMD and fractures. In this single-center study, 184 individuals (141 female subjects and 43 male subjects, mean age: 63.2 +/- 14.3 years) were recruited. In all, 149 of 184 could be genotyped by allele-specific polymerase chain reaction (PCR) for the VKORC1 variants 3673G>A or 9041G>A. The genotypes were correlated with clinical parameters. Vitamin K(1) concentrations were determined by high-performance liquid chromatography (HPLC); carboxylated (GlaOC) and undercarboxylated osteocalcin (GluOC) was determined by enzyme-linked immunosorbent assays (ELISAs). The 9041 GG and GA genotypes were significantly more frequent in patients with low BMD (P = 0.012). Thus, carriers of at least 1 G-allele seem to have a higher risk for low BMD. No statistically significant association was found for the 3673 G>A variant and BMD. GluOC concentrations were higher in patients who carried a 3673 GA and GG genotypes (P = 0.07). For both variants, no association with fractures could be observed. In our cohort, a genetic variation in the 3'-region of the VKORC1 gene (9041 AG and GG) was associated significantly with low BMD. This finding suggests that VKORC1 may play a role in osteoporosis. The results of our pilot study should be confirmed as our findings may be important for treatment decisions.