Background Despite its important role in many serious diseases, the genetic background for plasma YKL-40 has still not been systematically catalogued. Therefore, we aimed at identifying genetic variants in CHI3L1 influencing plasma YKL-40 levels in the general population.

Methods We resequenced the promoter, all 10 exons and exon-flanking intron segments of CHI3L1 in 904 individuals from the Danish general population (n=8899) with extreme plasma YKL-40 levels, adjusted for age. To potentially identify clinically important genetic variants with elevated plasma YKL-40 levels, we included twice as many individuals with the highest plasma YKL-40 levels (n=603) compared with the lowest plasma YKL-40 levels (n=301). Next, we mapped linkage disequilibrium for all variants with a minor allele frequency (MAF)>0.005. Finally, all participants were genotyped for eight variants that had divergent MAFs in the two extreme plasma YKL-40 groups.

Results We identified 59 genetic variants in CHI3L1. Fifteen of the genetic variants were associated with plasma YKL-40 levels. Three promoter SNPs, 1 non-synonymous SNP, and four intronic SNPs in CHI3L1 were associated with plasma YKL-40 levels at or below genome-wide association significance levels (unadjusted p for trend: from 4 × 10⁻⁸ to 6 × 10⁻²⁴³; age adjusted percentiles p for trend: from 3 × 10⁻¹² to 2 × 10⁻³⁰⁴).

Conclusions In a systematic search to identify genetic variants influencing plasma YKL-40 levels, we identified eight SNPs associated with plasma YKL-40 levels in the general population.