Genetically predicted vitamin K levels and risk of osteoarthritis: Mendelian randomization study

Osteoarthritis (OA) is a progressive disease for which there is no disease modifying therapy. Vitamin K levels and vitamin K antagonism have been associated with risk and progression of OA which may have direct implications for clinical management, but these observational findings are susceptible to confounding. We aimed to estimate the causal association between vitamin K and OA risk using Mendelian randomisation (MR). We used data from the largest genome-wide association study (GWAS) of OA to date (up to 826,690 individuals) to estimate the effect of genetically predicted vitamin K level (instrumented using four variants derived from a GWAS of 2,138 individuals) on risk of all OA types, knee, hip, spine, hand OA, and total joint replacement. We employed the inverse-variance weighted method for the primary analysis and, in a series of sensitivity analyses, adjusted for sub-genome wide significant instruments and tested for potential bias from pleiotropy. We showed that genetically predicted vitamin K levels were not causally associated with risk of OA overall (OR 0.98 per unit increase in log-transformed vitamin K1; 95%CI 0.96-1.01), knee (OR 0.98; 0.92-1.03), hip (OR 0.97; 0.88-1.07), spine (OR 0.97; 0.90-1.04), hand OA (OR 0.97; 0.91-1.04) or joint replacement (OR 0.96; 0.89-1.04). Results were similar across all sensitivity analyses. We found little evidence of a causal association between genetically predicted vitamin K and OA risk. Larger genetic and interventional studies of vitamin K are required to confirm our findings.