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.

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.

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.