Sequence Variation in Vitamin K Epoxide Reductase Gene Is Associated With Survival and Progressive Coronary Calcification in Chronic Kidney Disease

Abstract

Objective-Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ≤4 years. Approach and Results-This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ≤4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2-12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. Conclusions-Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival.These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease. These data suggest tissue-specific VKOR activity. Sequencing efforts by Rieder et al 10 have yielded 5 common haplotypes of VKORC1 that can be grouped into 2 evolutionarily distant groups called A and B. The A haplotype group is associated with attenuated expression of VKORC1 mRNA in the liver and, as a consequence, lower warfarin requirements.10 Conversely, the B haplotype group is associated with higher expression of VKORC1 mRNA in the liver and higher warfarin requirements. The focus of this study is the singlenucleotide polymorphism (SNP) rs8050894, which has been demonstrated to be in high linkage equilibrium and enables the distinction between these 2 groups. 21 To date, no study has examined the impact of sequence variations of VKORC1 in a CKD population.In this prospective cohort study, performed in a sample of individuals with CKD, we investigated the impact of genetic variations in VKORC1 on survival ≤4 years in a cohort of 167 predialysis stage 3 to 5 CKD patients. In a subset of 86 patients who had follow-up coronary artery calcification (CAC) quantified 4 years later, we examined the associations of sequence variations of VKORC1 on CAC progression. Our hypothesis was that the CC genotype that is associated with decreased warfarin requirements is a nonmodifiable risk factor for CAC and its progression and mortality in patients with CKD are based on low lifetime activity of the vitamin K cycle. Mate...

Vitamin K, Vascular Calcification, and Chronic Kidney Disease: Current Evidence and Unanswered Questions

“…This presents a critical barrier to establishing the importance of vitamin K to CKD patients for all the aforementioned reasons. Indirect evidence of the role of VKDPs in coronary calcification and survival in CKD was provided in a genetic analysis of 86 CKD patients with data on CAC and 4-y survival rates (77). The gene of interest was VKOR , which is a critical enzyme in the recycling of vitamin K (see Figure 4).…”

Bidirectional Translation in Cardiovascular Calcification

“…Importantly, this is not solely a pathology of drug side effects, as a threonine to alanine (Thr83Ala) polymorphism in MGP confers increased risk of CAC progression 58 . Emerging data suggesting sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzymatic target of warfarin, may also lend insight into high risk subpopulations of CAC progression and poorer survival rates 59 . While reports are mixed on the utility of phylloquinone (Vitamin K1) supplementation as a countermeasure to these pharmacological/biological side effects (which has been shown to both decrease 60 or increase risk of coronary artery calcification) 61 , a deeper understanding of interactions between drugs, genetics, and cardiovascular calcification will likely lead to novel potential therapeutic targets to slow progression of vascular calcification or counter significant side effects related to anticoagulation therapy.…”

VKORC1 rs2359612 and rs9923231 polymorphisms correlate with high risks of cardiovascular and cerebrovascular diseases

“…Multiple-recognized environmental factors including dyslipidemia, hypertension, diabetes mellitus, obesity, alcohol use, lack of physical activity, poor diet, tobacco use, and air pollution are linked to a high risk of CCVD (Kim and Johnston, 2011;Turin et al, 2012;Belanger et al, 2014). In light of the high incidence and mortality of CCVD, we are interested in the underlying mechanisms with an aim of identifying causative factors; thus, we noted recent studies that suggested the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene as a leading candidate in the genetic predisposition to CCVD risk (Kim and Johnston, 2011;Owens, 2011;Holden et al, 2014).…”