Indian J Med Res. 2013 Apr;137(4):734-41.
Relationship between VKORC1 single nucleotide polymorphism 1173C>T, bone mineral density & carotid intima-media thickness.
Fodor D, Bondor C, Albu A, Popp R, Pop IV, Poanta L.
Second Internal Medicine Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania.
BACKGROUND & OBJECTIVES: The effects of vitamin K-dependent proteins in bone mineralization and vascular calcification and the implication of vitamin K epoxide reductase gene (VKORC1) 1173C>T polymorphism in warfarin sensitivity are well known. The main objective of the study was to investigate the relationship between VKORC1 1173C>T polymorphism, bone mineral density (BMD), and atherosclerosis (evaluated by intima-media thickness of the carotid artery and the presence of calcified plaques) in patients suspected to have osteoporosis or osteopenia and referred for BMD determination.
METHODS: VKORC1 1173C>T polymorphism was evaluated in 239 consecutive patients referred by their physicians for BMD measurement (dual energy X-ray absorptiometry at L2-L4 lumbar spine, femoral neck and total hip). Ultrasonography of the carotid arteries was performed, intima-media thickness (IMT) was measured and the presence of atherosclerotic calcified plaques was recorded.
RESULTS: In the patients with osteoporosis and osteopenia there was a higher frequency of TT genotype of VKORC1 1173C>T (P=0.04). The TT genotype was significantly more frequent in the osteoporotic group compared to the osteopenic group (P=0.01). The mean age and body mass index were lower in the patients with normal BMD and TT genotype (P=0.02, P=0.03). There was no correlation between the IMT and VKORC1 1173C>T genotype but the TT genotype had a significant association with the presence of calcified atherosclerotic plaques (P=0.05). This finding was not correlated with normal or pathologic BMD.
INTERPRETATION & CONCLUSIONS: VKORC1 1173C>T polymorphism (TT genotype) was associated with osteoporosis and calcified plaques in the carotid artery in patients referred for BMD measurement. Different mechanisms are probably involved in these associations. TT genotype may serve as a potential genetic marker for the risk of OP and ATS.
The study of Fodor et al concerns the investigation of the role of vitamin K in bone metabolism and vascular health, analysing correlations between bone mineral density (BMD), carotid intima media thickness (IMT), atherosclerotic plaques with calcifications and the VKORC1 SNPs rs 993448 (VKORC1 1173C>T), in patients with osteoporosis (OP). The common mechanisms in the pathogenesis of OP and vascular calcifications are well known: age, chronic inflammation, smoking, diabetes mellitus, estrogen deficiency, hypovitaminosis (C, D, and K), free radicals, or renal failure. Many studies have demonstrated by now the association between OP and ATS, and the role of vitamin K in bone metabolism and vascular health.
Vitamin K acts as a cofactor for gamma-glutamyl carboxylase, being an electron donor for the conversion of some post-translational glutamyl residues, thus producing the gamma-carboxyglutamate (Gla). The main function of these Gla residues is to actively bind calcium, which is essential for the biological activity of the Gla containing proteins. The mediator in the recycle process of vitamin K 2,3 epoxide to the vitamin K hydroquinone is vitamin K epoxide reductase (VKOR). The vitamin K epoxide reductase gene (VKORC1) is situated on human chromosome 16p11.2 and encodes a protein of 163 amino acids with a mass of 18.2 kD13. Numerous single nucleotide polymorphisms (SNPs) were identified, the VKORC1 gene being highly polymorphic. One of these SNPs, rs 993448 or VKORC1 1173C>T was studied in many studies. But it still remains unclear if there is a common VKORC1 SNPs that can be considered a risk factor for both OP and ATS, and if there is a common pathway for the intervention, in this polymorphism.
Fodor et al found that in patients with osteoporosis and osteopenia there was a more frequent TT genotype of VKORC1 1173C>T. Further, the TT genotype was significantly more frequently found in the osteoporotic group compared to the osteopenic group. For the whole group of patients no correlation could be established between the IMT and VKORC1 1173C>T genotype but, when they analyzed the presence of calcified atherosclerotic plaques, there was a significant association with the TT genotype (P=0.05). This finding was not associated with normal or pathologic BMD. In this study it was used a recessive model (TT versus CT or CC genotype for the VKORC1 1173C>T genetic polymorphism). They also showed that patients with TT genotype were younger, suggesting that their BMD had become abnormal earlier and OP had appeared at a younger age. Also, the lower BMI of TT genotype patients compared to other genotypes should be interpreted as a risk factor for developing OP. As a general conclusion, VKORC1 polymorphism (TT genotype) was associated with OP and the presence of calcified plaques in the carotid artery, with different mechanisms involved in these associations.
Acknowledgment: Authors acknowledge the ANCS (Romanian National Authority for Scientific Research) 42107/2008 PNII grant, for financial support.