VKORC1 and CYP2C9 Polymorphisms: A Case Report in a Dutch Family with Pulmonary Fibrosis

Abstract

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.

Keywords: familial idiopathic pulmonary fibrosis; oxidative stress; polymorphism; vitamin K supplementation.

Figure 1

Pedigree of the studied family. Actual genotypes are listed in Table 1.

Figure 2

Vitamin K cycle with influences. The role of vitamin K epoxide reductase (VKORC1) and the cytochrome P450 iso-enzyme 2C9 (CYP2C9) in coagulation: VKORC1, as well as the vitamin K quinone reductase (VKQR), is involved in reducing steps in the generation of the active hydroquinone form of vitamin K. Inhibition or diminished activity of CYP2C9 leads to a decreased breakdown and subsequent excretion of food-derived VKORC1-inhibiting coumarins. Presence of polymorphisms and inhibition of VKORC1 reduces vitamin K activity, viz. carboxylation of glutamic acid (GLU) into calcium-binding gamma-glutamic acid residues (GLA). In addition, polymorphisms and inhibition of CYP2C9 by oral contraceptives or antifungal agents might decrease the breakdown of VKORC1 inhibiting compounds. Decreased VKORC1 activity has been associated with the occurrence of fibrosis.