Plasma levels of the proinflammatory chitin-binding glycoprotein YKL-40, variation in the chitinase 3-like 1 gene (CHI3L1), and incident cardiovascular events.

BACKGROUND

YKL-40, encoded by the chitinase 3-like 1 (CHI3L1) gene, is a chitinase-like protein involved in innate immune function hypothesized to play a role in the progression of atherosclerosis that may have differential roles in myocardial infarction (MI), as compared to stroke.

RESULTS

In a nested case-control study conducted within a prospective cohort of 23 294 initially healthy women of European ancestry, we (1) measured plasma concentration of YKL-40 among 359 participants who subsequently developed cardiovascular events and among 359 age-, smoking-, and hormone replacement therapy-matched participants who remained free of disease during 17 years of follow-up, (2) compared effects of YKL-40 on vascular risk to that associated with 3 alternative inflammatory biomarkers (high-sensitivity C-reactive protein) ([hsCRP], soluble intracellular adhesion molecule 1, and fibrinogen), and (3) evaluated the role of 41 single-nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 gene (CHI3L1) as determinants of YKL-40 levels and incident vascular events. YKL-40 levels were higher in women with hypertension, diabetes, and obesity and correlated modestly with high-density lipoprotein cholesterol, triglycerides, and hsCRP, but not with low-density lipoprotein cholesterol. Baseline YKL-40 level was significantly associated with incident thromboembolic stroke with a magnitude of effect (a 40% per quartile increase in odds ratio [OR], P=0.019) comparable to that of hsCRP (a 52% per quartile increase in OR, P=0.006). By contrast, no significant association was observed between YKL-40 and incident MI. Genetic variation in CHI3L1 was strongly associated with YKL-40 levels; however, in this sample set, we did not observe a statistically significant association between genotype and future vascular events.

CONCLUSIONS

Among initially healthy U.S. women, plasma levels of the proinflammatory chitenase-like protein, YKL-40, were influenced by environmental as well as genetic factors and predicted incident thromboembolic stroke, but not MI, a differential effect consistent with limited previous data.