Genetic Variants Influencing Vitamin K

WCRJ 2016; 3 (1): e649 GENETIC VARIANTS INFLUENCING VITAMIN K A. RAINONE1, S.R. SIESTO1, M. D’URSO2, N. MAZZARELLA2, S. PUGLIESE3, C. MANAGO4, A. STEFFAN5 1GORI, Gruppo Oncologi Ricercatori Italiani, Onlus, Pordenone, Italy 2Italian Association of Pharmacogenomics and Molecular Diagnostics, Caserta, Italy 3Research Center CETAC, Caserta, Italy 4Dipartimento di Igiene, AOU Policlinico V. Emanuele, Catania, Italy 5Department of Oncology-Haematology, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy Abstract – There are two forms of natural vitamin K, phylloquinone and menaquinone. Phyl- loquinone, vitamin K1, is the major type of dietary vitamin K, which is present in high amounts in green vegetables, while menaquinone, vitamin K2, is synthesized by the human intestinal bacteria. Furthermore, a synthetic type of vitamin K is known: vitamins K3. Vitamin K-dependent proteins require carboxylation of certain glutamate residues for their biological functions such as blood coagulation (factor II, VII, IX, X and proteins C, S and Z), bone metabolism (osteocalcin) and vascular biology. Without vitamin K, blood coagulation is impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries. The aim of this study is to examine how genetic variations influence responses to oral anticoagulant therapy. There is a large variability in response to anticoagulant therapy, and this can modify the benefit/risk ratio of drugs. This variability can be explained by clinical factors such as age, sex, demographic and environmental factors, inter- and intra-individual variability and genetic variants. In recent years, several genetic polymorphisms have been associated with variable biological responses to oral anticoagulants. KEYWORDS: CYP2C9, VKORC1, CY4F2, Pharmacogenomics. INTRODUCTION by intestinal microbiota. The intestinal production of Vitamin K2 is usually enough to cover the daily Vitamin K is an essential vitamin. It is one of the requirements, and it is the main form stored in the four fat-soluble vitamins as well as vitamins A, D, liver (about 90% of the total). Another synthetic E. Vitamin K, phylloquinone and menaquinone, type of vitamin K is known as vitamins K3 or includes some derivatives naftoquinonic soluble. menadione, which is partially soluble in water. Phylloquinone, vitamin K1, is the major type Menadione is a synthetic naphthoquinone without of dietary vitamin K, which is present in high the isoprenoid side chain and biological activity, amounts in green vegetables (spinach, cabbage, but it can be converted to active vitamin K2 by tomatoes). Menaquinone, vitamin K2, is produced alkylation in vivo. Corresponding Author: Aniello Rainone, MD; e-mail: [email protected] 1 GENETIC VARIANTS INFLUENCING VITAMIN K Vitamin K participates in the ordinary process vitamin K3 in radiotherapy with EGFR inhibitors of blood clotting, and its deficiency causes bleeding. erlotinib and cetuximab, and a case study on the The blood clotting requires the carboxylation of usefulness of vitamin K3 (menadione) as against certain glutamate residues of the protein prothrombin of pancreatic cancer. into γ-carboxyprothrombin so that it can bind to other factors. Carboxylation is catalyzed by the enzyme y-glutamyl carboxylase (GGCX) which VITAMIN K METABOLIC FATE requires three co-substrates: reduced vitamin K, CO2, and O2. Carboxylation requires the abstraction Vitamin K was discovered fortuitously in 1929 as of a proton from the 4-carbon of glutamate by part of experiments on sterol metabolism and was reduced vitamin K and results in the conversion immediately associated with blood coagulation. of vitamin K to vitamin K epoxide. The vitamin It was named vitamin K because of the German K epoxide must be recycled to vitamin K before word “koagulation”. being reused, and this reaction is catalyzed by the The four vitamin K-dependent procoagulants enzyme vitamin K epoxide reductase (VKOR). (factor II or prothrombin, and factors VII, IX, and The four vitamin K-dependent procoagulants X) are serine proteases synthesized in the liver and (prothrombin, and factors VII, IX, and X) are then secreted into the circulation as inactive forms serine proteases that are synthesised in the liver and (zymogens)2. Their biologic activity is dependent then secreted into the circulation as inactive forms on the normal complement of Gla residues, which (zymogens). The vitamin K in the diet, mainly are capable chelators of calcium ions. In the as phylloquinone, is absorbed in the proximal presence of Gla and calcium ions these proteins intestine due to bile salts contained in pancreatic bind to the phospholipids of surface membrane juice. At the level of the intestinal mucosa, vitamin of platelets and endothelial cells where, together K is incorporated into chylomicrons, secreted into with other cofactors, they form membrane-bound the lymph and introduced into the bloodstream. enzyme complexes. The zymogens of the four Circulating phylloquinone is associated with vitamin K-dependent clotting factors are cleaved lipoprotein (LDL and VLDL), and only a small to yield the active protease clotting factors3. part is transported in free form. The liver is The protein S and protein C (other vitamin responsible for the reactivation of the vitamin K-dependent proteins) play a narrow role in the by the action of the hepatic vitamin K epoxide inhibition of coagulation. The role of protein C reductase. So, if liver function is normal, the is to degrade phospholipid-bound of activated vitamin is effectively recovered and, since the factors V and VIII in the presence of calcium. intestinal microbiota synthesizes vitamin K, the Protein S acts as a synergistic cofactor to protein daily requirements are satisfied. C by enhancing the binding of activated protein Deficiencies can occur due to inadequate lipid C to negatively charged phospholipids. Another absorption, intestinal dismicrobism and liver vitamin K-dependent protein described in human disease. Moreover during fetal development, in 1984 is Protein Z4. Protein Z (PZ) is a vitamin placental transfer of vitamin K is low, leading to K-dependent factor but it has no enzymatic an exogenous deficiency of vitamin K in newborns activity. The structure of protein Z shows wide secondary to low substrate intake. Newborns’ homology with many coagulation factors, such as main dietary intake of vitamin K is either through VII, IX, X, and protein C. However, in contrast breast milk or commercially available infant to other vitamin K-dependent coagulation factors, formula; breast milk contains significantly lower protein Z is not a serine protease because of levels of vitamin K than does commercial formula. the lack of the active centre in its amino acid Therefore, insufficient dietary intake of vitamin sequence. It is a cofactor of a serpin, the protein K continues after birth, especially in exclusively Z-dependent protease inhibitor (ZPI), and the breastfed infants. Recommended prophylaxis of complex PZ/ZPI inhibits activated factor X on vitamin K by injection in the newborn period phospholipid surfaces5,6. Its plasma concentration replaces physiologically low vitamin K1 levels spans a very wide range in normal individuals and decreases the risk of vitamin K deficiency and its plasma concentration is greatly reduced associated hemorrhage1. In addition to these during oral anticoagulation7. Despite conflicting classical applications, recently vitamin K3 or results, a recent meta-analysis indicated that PZ menadione is used to protect the skin from the deficiency could be a risk for venous and arterial secondary toxicity caused by radiation therapy thrombosis and early fetal loss8. However, these B with EGFR inhibitors (Epidermal growth factor conclusions are drained from case-control studies receptor). In this regard, we want to bring back two of small size, constituting a significant limitation. case studies. A case study of the effectiveness of Recently, it has been shown that PZ and/or ZPI are 2 GENETIC VARIANTS INFLUENCING VITAMIN K synthesised by normal kidney and different cancer The difficulty in managing oral anticoagulants cells, suggesting that the complex PZ/ZPI might is strongly associated to the narrow therapeutic play a role in inhibiting the tissue deposition of index range of Warfarin and acenocoumarol and fibrin9-11. The physiopathological consequences of to the great inter- and intra-individual variability these observations remain to be recognized. in response to the treatment. This is estimated by measuring the International Normalized Ratio (INR), sensitive to clotting factors deficiencies VITAMIN K AND ANTICOAGULATION (factors II, VII and IX, three of the VK-dependent clotting factors). Beside with demographic and Warfarin, a coumarin derivative, produces an environmental factors, genetic polymorphisms anticoagulant effect by interfering with the have also been identified, explaining the reason interconversion cyclic of vitamin K and its 2,3 for the unpredictability in response to oral epoxide (vitamin K epoxide). Vitamin K is anticoagulant therapy14. To date, genetic variants a cofactor for the carboxylation of glutamate influencing the vitamin K pathway include the key residues to γ-carboxyglutamates (Gla) on the genes (Figure 1): a) vitamin K Epoxide reductase C1 N-terminal regions of vitamin K-dependent (VKORC1), b) cytochrome-P450 2C9 (CYP2C9); proteins. By inhibiting the vitamin K conversion and c) cytochrome-P450 4F2 (CYP4F2). cycle, warfarin

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