BACKGROUND: We tested the hypothesis that observationally and genetically increased YKL-40 concentrations are associated with alcoholic liver and pancreas damage and disease.

METHODS: We performed cohort and mendelian randomization in 86,258 individuals from the Danish general population, with measured concentrations of plasma YKL-40 (n = 21 646) and CHI3L1 rs4950928 genotype (n = 84 738).

RESULTS: Increased YKL-40 was associated with increased alanine aminotransferase, bilirubin, alkaline phosphatase, γ-glutamyl transferase, erythrocyte mean corpuscular volume, C-reactive protein, and fibrinogen and with decreased albumin; coagulation factors II, VII, and X; and pancreatic amylase. The multifactorially adjusted hazard ratio for alcoholic liver cirrhosis comparing the 96%-100% vs 0%-33% YKL-40 percentile categories was 41 (95% CI 14-118). Corresponding ratios were 7.9 (5.1-12) for any alcoholic liver disease, 4.1 (1.7-10) for alcoholic pancreatitis, and 3.4 (1.9-6.1) for any pancreatitis. CHI3L1 rs4950928 genotype explained 14% of the variation in plasma YKL-40 concentrations but was not associated with alcoholic liver and pancreas damage or disease. A doubling in YKL-40 concentrations was associated with a multifactorially adjusted observational hazard ratio of 2.8 (2.4-3.3) for alcoholic liver cirrhosis and a corresponding genetic odds ratio of 1.1 (0.7-1.5). Corresponding risk estimates were 2.0 (1.8-2.2) observationally and 1.0 (0.8-1.1) genetically for any alcoholic liver disease, 1.4 (1.1-1.9) observationally and 1.1 (0.8-1.5) genetically for alcoholic pancreatitis, and 1.3 (1.1-1.6) observationally and 1.0 (0.8-1.3) genetically for any pancreatitis. Excessive alcohol consumption combined with YKL-40 concentrations in the top 5% was associated with 10-year risk of alcoholic liver cirrhosis of up to 7% in ever-smokers and 2% in never-smokers.

CONCLUSIONS: YKL-40 concentration within the top 5% was a marker for alcoholic liver cirrhosis, with no evidence to support a causal relationship.