rs2297839 — CHI3L1 CHI3L1 Intron Variant

CHI3L1's Intronic Dimmer: Lower YKL-40, Lower Inflammation

The CHI3L1 gene encodes YKL-40, a chitinase-like glycoprotein that functions as a biomarker and mediator of tissue inflammation. Elevated YKL-40 is a consistent feature of active asthma, allergic airway disease, and cardiovascular inflammation; levels track with disease severity across all three domains. The CHI3L1 locus on chromosome 1q32.1 contains a cluster of genetic variants — each contributing independently to how much YKL-40 your body produces. rs2297839 is an intronic variant at this locus that co-associates with lower YKL-40 levels, adding a third independent regulatory signal alongside the well-characterized promoter (rs4950928) and upstream eQTL (rs10399931) variants.

The Mechanism

rs2297839 sits within the body of the CHI3L1 gene at chr1:203183056 (GRCh38), approximately 3.7 kb from the main promoter variant rs4950928. The variant is annotated as intronic on the minus-strand gene. The precise molecular mechanism by which rs2297839 influences CHI3L1 expression has not been published in isolation — it was identified as a tag SNP among 15 CHI3L1 variants in a population study rather than through a dedicated functional assay. However, its co-classification with four other CHI3L1 variants (rs10399931, rs1538372, rs2071580, rs4950928) as YKL-40-lowering alleles in Xu et al. 2021¹¹ Xu et al. 2021
Xu T et al. Association of CHI3L1 gene variants with YKL-40 levels and hypertension incidence. J Cell Mol Med, 2021 indicates it is part of the same regulatory architecture. The T allele at rs2297839 is consistently associated with lower circulating YKL-40, mirroring the effect of protective alleles at rs4950928 and rs10399931.

Intronic variants can modulate gene expression through several mechanisms: altering splicing enhancer or silencer sequences²² splicing enhancer or silencer sequences
Intronic regulatory elements that recruit splicing factors, affecting which exons are included in the final mRNA, disrupting chromatin loop anchor points, or tagging functional variants in linkage disequilibrium. Given that the Guerra et al. birth cohort study found that CHI3L1 alleles linked to lower YKL-40 are associated with higher DNA methylation at five CpG sites, epigenetic mediation is a plausible route for rs2297839 as well.

The Evidence

The primary evidence for rs2297839 comes from a nested case-control study by Xu et al.³³ nested case-control study by Xu et al.
Xu T et al. Association of CHI3L1 gene variants with YKL-40 levels and hypertension incidence: A population-based nested case-control study in China. J Cell Mol Med, 2021 of 507 matched case-control pairs within a Chinese prospective cohort. Among 15 CHI3L1 tag SNPs, rs2297839 was one of five variants associated with lower YKL-40 levels. In the male sub-analysis, heterozygous and rare homozygous T-allele carriers had a significantly lower risk of hypertension compared with major homozygote (CC) carriers (OR 0.49, 95% CI 0.26–0.91).

The biological plausibility rests on the well-established role of YKL-40 in vascular inflammation. Lee et al. 2010⁴⁴ Lee et al. 2010
Lee C-G et al. Role of breast regression protein-39/YKL-40 in asthma and allergic responses. J Allergy Clin Immunol, 2010 demonstrated that YKL-40 activates macrophages, promotes Th2 polarization, and drives tissue remodeling — mechanisms relevant to both airway disease and atherosclerosis. Lower genetically-determined YKL-40 should therefore dampen inflammatory signaling across multiple tissue compartments.

It is important to note that rs2297839 has only one direct study, and the hypertension association was limited to male subjects in a Chinese cohort. Independent replication in diverse populations and dedicated functional characterization are needed before the evidence level can be upgraded beyond emerging.

Practical Actions

For CC homozygotes, the genotype represents the common YKL-40-higher baseline, shared by approximately 64% of people globally. Serum YKL-40 is the most direct readout of combined CHI3L1 genetic status — useful for tracking inflammatory activity in asthma, COPD, or cardiovascular workups.

For CT and TT carriers, the T allele is associated with a lower inflammatory setpoint at this locus. In a clinical YKL-40 result, T-allele carriers at rs2297839 — especially when combined with protective alleles at the promoter (rs4950928 GG) or eQTL (rs10399931 TT) — are likely to show lower-than-average values that reflect their genetics rather than a pathological deficiency.

Interactions

rs2297839 operates within the same CHI3L1 regulatory cluster as rs4950928 (promoter, the strongest YKL-40 determinant), rs10399931 (upstream regulatory, acts via a post-transcriptional mechanism), and rs872129 (a third independent eQTL signal confirmed by conditional analysis in Chou et al. 2024). The intronic variant rs12141494 adds a fourth independent signal that specifically affects airway tissue YKL-40 and lung function severity in asthma. Each variant in this cluster represents a partial contribution to the genetic YKL-40 set-point — carriers of protective alleles at multiple CHI3L1 variants benefit from additive suppression of this inflammatory axis.