Observationally and Genetically High YKL-40 and Risk of Venous Thromboembolism in the General Population: Cohort and Mendelian Randomization Studies.

Abstract

High baseline YKL-40 is associated with later development of ischemic stroke, but not with myocardial infarction. Whether high YKL-40 levels are associated with increased risk of venous thromboembolism is presently unknown. We tested the hypothesis that observationally and genetically high YKL-40 is associated with increased risk of venous thromboembolism in the general population. Cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (N=21 647) and CHI3L1 rs4950928 genotype (N=94 579). From 1977 to 2013, 1489 individuals developed pulmonary embolism, 2647 developed deep vein thrombosis, and 3750 developed venous thromboembolism (pulmonary embolism and deep vein thrombosis). For the 91% to 100% versus 0% to 33% YKL-40 percentile category, the multifactorially adjusted hazard ratio was 2.38 (95% confidence interval, 1.25-4.55) for pulmonary embolism, 1.98 (1.09-3.59) for deep vein thrombosis, and 2.13 (1.35-3.35) for venous thromboembolism. Compared with rs4950928 GG homozygosity, presence of C-allele was associated with a doubling (CG) or tripling (CC) in YKL-40 levels, but not with risk of venous thromboembolism. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for pulmonary embolism of 1.17 (1.00-1.38) and a genetic odds ratio of 0.97 (0.76-1.23). Corresponding risk estimates were 1.28 (1.12-1.47) observationally and 1.11 (0.91-1.35) genetically for deep vein thrombosis and 1.23 (1.10-1.38) observationally and 1.08 (0.92-1.27) genetically for venous thromboembolism. High YKL-40 levels were associated with a 2-fold increased risk of venous thromboembolism, but the association was not causal.