rs10399931 — CHI3L1 CHI3L1 eQTL Partner Variant

YKL-40's Second Switch: The eQTL Partner Variant

The CHI3L1 gene encodes YKL-40, one of the most clinically informative biomarkers of tissue inflammation — elevated in asthma, COPD, rheumatoid arthritis, and coronary artery disease. How much YKL-40 your body produces is largely genetically predetermined, and the CHI3L1 locus on chromosome 1q32.1 contains multiple independent regulatory variants that each contribute to this set-point. rs10399931 is one of those variants — a 2 kb upstream regulatory SNP that modulates CHI3L1 mRNA levels independently of the primary promoter variant (rs4950928), adding a distinct layer of genetic control over the inflammatory YKL-40 axis.

The Mechanism

rs10399931 lies ~2,000 base pairs upstream of the CHI3L1 transcription start site, in a region with regulatory potential. Unlike the promoter SNP rs4950928, which alters a transcription factor binding site, rs10399931 appears to operate through a post-transcriptional mechanism¹¹ post-transcriptional mechanism
The T allele reduces CHI3L1 mRNA abundance without altering promoter-level reporter activity, implying effects on mRNA stability, splicing-associated regulation, or upstream chromatin context rather than direct promoter binding. The common C allele (plus strand, ~73% globally) is associated with higher CHI3L1 mRNA levels and consequently higher circulating YKL-40. The rarer T allele (~27%) reduces mRNA expression and lowers the YKL-40 set-point.

The Guerra et al. birth cohort study²² Guerra et al. birth cohort study
Guerra S et al. Genetic and epigenetic regulation of YKL-40 in childhood. J Allergy Clin Immunol, 2018 studied 68 CHI3L1 SNPs in up to 2,405 children and identified rs10399931 among 7 variants independently associated with YKL-40. Critically, alleles linked to lower YKL-40 (including the T allele at rs10399931) were associated with higher DNA methylation at five CHI3L1 CpG sites, suggesting the genetic effect is partly mediated through epigenetic remodeling — an upstream regulatory SNP shaping chromatin accessibility at the CHI3L1 locus.

The Evidence

The Taiwanese population study by Tsai et al.³³ Tsai et al.
Tsai Y et al. CHI3L1 polymorphisms associate with asthma in a Taiwanese population. BMC Med Genet, 2014 genotyped rs10399931 in 628 asthma patients and controls. The CC genotype (plus-strand, equivalent to the paper's "GG" in minus-strand gene notation) was significantly associated with asthma risk (aOR=1.77, 95% CI 1.13–2.77) and the highest serum YKL-40 levels (133 ng/mL vs 91 ng/mL for TT carriers). YKL-40 levels in CC carriers correlated with FEV1 decline (P=0.004) and FVC reduction (P=0.011), and this effect persisted even among patients on inhaled corticosteroids — suggesting rs10399931-linked YKL-40 elevation is refractory to standard anti-inflammatory therapy.

A meta-analysis across 16 publications involving 5,005 cases and 9,725 controls⁴⁴ 16 publications involving 5,005 cases and 9,725 controls
Huang QP et al. Assessment of the Association between Genetic Polymorphisms in the CHI3L1 Gene and Asthma Risk. Int Arch Allergy Immunol, 2022 confirmed that the TT genotype is protective against asthma in East Asian populations (TT vs CC: OR=0.77, 95% CI 0.61–0.98, P=0.030), with population allele frequencies making this signal particularly detectable in Asian cohorts.

A functional study by Chen et al.⁵⁵ Chen et al.
Chen G et al. Functional study of the association of CHI3L1 polymorphisms with asthma susceptibility in the Southwest Chinese Han population. Biosci Rep, 2019 directly measured mRNA expression in human subjects — CT/TT genotype carriers showed significantly reduced CHI3L1 mRNA (P=0.002), establishing molecular causality.

In the coronary artery disease context, Chou et al.⁶⁶ Chou et al.
Chou HH et al. Circulating YKL-40 levels but not CHI3L1 or TRIB1 gene variants predict long-term outcomes in multivessel CAD. Sci Rep, 2024 used conditional analysis to confirm rs10399931 as an independent YKL-40 determinant at the CHI3L1 locus, distinct from rs4950928 — meaning the two variants capture separate genetic contributions to YKL-40 variation.

Practical Actions

For CC carriers, the practical implications mirror those of the rs4950928 CC genotype: an elevated YKL-40 baseline reflects a higher inflammatory setpoint. However, because rs10399931 acts at a different regulatory level than rs4950928, a CC carrier at this locus who also carries CG or GG at rs4950928 has a compound picture — neither variant alone describes the full genetic contribution to their YKL-40 level. Serum YKL-40 testing is the direct readout of both variants together.

For TT carriers, the low-YKL-40 genotype confers partial protection against asthma and airway inflammation, but because TT is uncommon (~7%), clinical reference ranges are calibrated to the CC majority and may flag TT-typical low values as anomalous.

Interactions

rs10399931 operates in the same YKL-40 QTL cluster as rs4950928 (the primary CHI3L1 promoter variant, also in related_snps here) and rs872129, which each contribute independent signals to circulating YKL-40 levels confirmed by sequential conditional analyses (Chou et al. 2024, PMID 39592699). The intronic variant rs12141494 independently affects airway tissue YKL-40 expression and lung function, adding a fourth distinct CHI3L1 regulatory layer. Together, these variants can substantially compound or offset one another's contributions to the inflammatory setpoint.