title: Vitamin K epoxide reductase (VKORC1) gene mutations in osteoporosis: A pilot study.
abstract: 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.
authors.affiliation: Department of Orthopedics, Medical University of Vienna, A-1097 Vienna, Austria.
authors.forename: Gerold
authors.initials: G
authors.lastname: Holzer
authors.forename: Anna Verena
authors.initials: AV
authors.lastname: Grasse
authors.forename: Sonja
authors.initials: S
authors.lastname: Zehetmayer
authors.forename: Peter
authors.initials: P
authors.lastname: Bencur
authors.forename: Christian
authors.initials: C
authors.lastname: Bieglmayer
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
mesh_terms: D000368:Aged; D015519:Bone Density / Q000235:genetics; D005260:Female; D050723:Fractures, Bone / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D015675:Osteocalcin / Q000097:blood / Q000378:metabolism; D010024:Osteoporosis / Q000201:enzymology / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D010837:Vitamin K 1 / Q000097:blood; D064417:Vitamin K Epoxide Reductases
chemical_list: D012333:RNA, Messenger; D015675:Osteocalcin; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases