rs872129 — CHI3L1 CHI3L1 eQTL Variant

Third independent eQTL signal at the CHI3L1/YKL-40 locus on chromosome 1q32.1; the G allele modifies circulating YKL-40 levels independently of the two primary CHI3L1 regulatory variants and has been linked to altered inflammatory and cerebrovascular risk

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YKL-40's Third Genetic Switch: The CHI3L1 eQTL Cluster

The CHI3L1 gene encodes YKL-40, a 40-kDa secreted glycoprotein produced by macrophages, neutrophils, and epithelial cells during inflammation. Elevated circulating YKL-40 marks active tissue remodeling and chronic inflammation — it is elevated in asthma, COPD, rheumatoid arthritis, coronary artery disease, and several inflammatory malignancies. How much YKL-40 your body produces is predominantly determined by genetics, and the CHI3L1 locus on chromosome 1q32.1 contains at least three independent regulatory variants that together account for a substantial fraction of interindividual YKL-40 variation. rs872129 is one of these three — the third independent signal confirmed by conditional analysis after the primary promoter variant (rs4950928) and its upstream partner (rs10399931) have already been accounted for.

The Mechanism

rs872129 lies in the genomic neighborhood of CHI3L1 at chr1:203200263, approximately 13.5 kb from the CHI3L1 transcription start site. NCBI does not annotate it within a defined gene boundary, but GWAS conditional analysis in the Taiwan Biobank cohort establishes it as a cis-eQTL11 cis-eQTL
A cis-acting expression quantitative trait locus: a genetic variant that influences the expression level of a nearby gene by altering regulatory elements such as enhancers, chromatin accessibility, or transcription factor binding sites at that locus for CHI3L1 — meaning variation at rs872129 independently affects CHI3L1 mRNA output or transcript stability, independent of the two other known CHI3L1 eQTL variants.

The A allele (plus strand, ~86% globally) is the GRCh38 reference and the common population baseline. The G allele (~14% globally; ~53% in East Asian populations) is the minor variant that modulates CHI3L1 regulatory activity at this position. Unlike the established directionality of rs4950928 (C = higher YKL-40) and rs10399931 (C = higher YKL-40), the precise molecular direction of the rs872129 G allele effect on YKL-40 levels is not yet characterized in a large-scale functional study. The Rathcke 2012 observational data associate G homozygosity with adverse outcomes, and the eQTL role is confirmed, but the specific quantitative effect on YKL-40 requires further study.

The Evidence

The discovery of rs872129 as an independent CHI3L1 signal was established by Chou et al.22 Chou et al.
Chou HH et al. Circulating YKL-40 levels but not CHI3L1 or TRIB1 gene variants predict long-term outcomes in patients with angiographically confirmed multivessel coronary artery disease. Sci Rep, 2024 in a GWAS of 4,664 Taiwan Biobank participants. After adjusting for rs4950928 and then rs10399931, rs872129 emerged as a statistically significant independent predictor of circulating YKL-40, establishing the three-variant architecture of the YKL-40 quantitative trait locus. These findings were validated in a separate CAD cohort of 521 patients. Importantly, the combined weighted genetic risk score from all three CHI3L1 variants did not independently predict mortality or MACE over 3.7 years — whereas actual circulating YKL-40 protein levels did (log-rank P=9.58×10⁻⁸ for all-cause mortality). This underscores that the genetic variants set the long-term YKL-40 baseline; measured protein levels reflect that baseline plus current inflammatory activity, and it is the combination that drives outcomes.

In a prospective cohort study, Rathcke et al.33 Rathcke et al.
Rathcke CN et al. Variations of CHI3L1, levels of the encoded glycoprotein YKL-40 and prediction of fatal and non-fatal ischemic stroke. PLoS One, 2012 genotyped 12 CHI3L1 SNPs — including rs872129 — in 2,656 Danish adults followed for 15 years. Minor allele (G) homozygosity at rs872129 was rare in this European-ancestry cohort (0.5% of participants, N=12 individuals) but was associated with markedly elevated fatal ischemic stroke risk (HR=9.35, 95% CI 1.25–69.87, P=0.022). The very wide confidence interval reflects the small sample; the finding should be interpreted cautiously as a hypothesis-generating signal rather than a definitive risk estimate. It is biologically plausible through the YKL-40 axis: elevated YKL-40 promotes vascular smooth muscle proliferation, macrophage foam cell formation, and endothelial dysfunction — all relevant to thromboembolic stroke.

The foundational biology of the YKL-40 axis is established by Ober et al.44 Ober et al.
Ober C et al. Variation in the CHI3L1 gene influences serum YKL-40 levels, risk of asthma, and lung function. N Engl J Med, 2008 and the broader CHI3L1 eQTL architecture is confirmed in European children by Guerra et al.55 Guerra et al.
Guerra S et al. Genetic and epigenetic regulation of YKL-40 in childhood. J Allergy Clin Immunol, 2018.

Practical Actions

The most direct readout of all three CHI3L1 eQTL variants simultaneously is serum YKL-40 protein measurement. For AG and GG carriers at rs872129, the G allele contributes an additional regulatory perturbation at the CHI3L1 locus on top of whatever genotype is present at rs4950928 and rs10399931. Serum YKL-40 integrates all three signals and provides a single actionable number — a rise above personal baseline (rather than a cross-population threshold) is the most clinically meaningful signal.

For GG homozygotes specifically — especially relevant in East Asian populations where GG frequency may be ~28% — the Rathcke data suggest heightened cerebrovascular vigilance is warranted, with the caveat that the sample was small and the biological mechanism needs replication.

Interactions

rs872129 operates in the same YKL-40 QTL cluster as rs4950928 (CHI3L1 promoter, primary signal) and rs10399931 (upstream regulatory, second signal), all confirmed as independent contributors to circulating YKL-40 by Chou et al. 2024 (PMID 39592699). The intronic variant rs12141494 (CHI3L1 intron 6) adds a fourth distinct regulatory layer that specifically controls airway tissue YKL-40 expression and lung function in asthma (Gomez et al. 2015, PMID 25592985). Together these four CHI3L1 variants capture the known genetic architecture of YKL-40 determination and can compound substantially in individuals inheriting risk alleles at multiple positions.

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard YKL-40 Producer Normal

Common genotype — standard YKL-40 production at this CHI3L1 regulatory locus

The AA genotype at rs872129 was identified in the Chou et al. 2024 Taiwan Biobank GWAS (n=4,664) as the common baseline state at the third independent CHI3L1 eQTL signal. Conditional GWAS analysis confirmed that rs872129 contributes a statistically independent effect on YKL-40 levels distinct from both the promoter effect of rs4950928 and the mRNA-level effect of rs10399931.

In European-ancestry populations, A is extremely common (~90%), making the AA genotype the vast majority. In East Asian populations, A frequency is ~47%, so AA is less dominant and AG/GG are more prevalent. The Rathcke 2012 study in 2,656 Danish adults found that only 0.5% were GG homozygotes (N=12), with the remaining ~99.5% being AA or AG — confirming that AA is the strongly predominant European genotype.

AG Intermediate CHI3L1 Modifier Intermediate

One G allele modifies CHI3L1 regulatory activity at this locus; clinical significance is emerging

The AG genotype places you as a carrier of the G allele — the minor variant that Chou et al. 2024 confirmed as an independent predictor of YKL-40 levels in the Taiwan Biobank conditional GWAS. The directionality of the G allele's effect (whether it raises or lowers YKL-40 relative to AA) has not been established with precision; the Rathcke 2012 data associate G homozygosity with adverse cerebrovascular outcomes (elevated stroke mortality risk), suggesting the G allele may raise rather than lower the YKL-40 setpoint — but this requires confirmation in a larger cohort.

Because rs872129 is the third independent CHI3L1 signal, its effect in AG heterozygotes is expected to be meaningful but modest relative to the primary variants at rs4950928 and rs10399931. Serum YKL-40 protein measurement directly captures the integrated output of all three variants together.

GG Homozygous G Carrier High Risk

Two G alleles — rare genotype with emerging signal for elevated cerebrovascular risk through the YKL-40 axis

The GG genotype at rs872129 is the homozygous minor allele state confirmed as a significant CHI3L1 eQTL by Chou et al. 2024 in Taiwan Biobank conditional GWAS analysis. Its rarity in European-ancestry populations (0.5%, N=12 in Rathcke 2012) makes precise risk quantification difficult — the HR=9.35 for fatal ischemic stroke carries a very wide confidence interval (1.25–69.87) that encompasses substantial uncertainty.

In East Asian populations, where G frequency is ~53%, GG homozygotes represent approximately 28% of individuals — a far more tractable frequency for population study. The near-absence of large-scale East Asian functional data for this specific variant means the risk estimate from the small Danish cohort should be viewed as a hypothesis-generating signal awaiting replication.

The YKL-40 mechanism provides biological plausibility: YKL-40 activates downstream inflammatory cascades through IL-13Rα2, TLR4, and MAPK pathways, promotes macrophage foam cell formation in atherosclerotic plaques, and stimulates vascular smooth muscle proliferation — all processes that increase risk of thromboembolic stroke. Whether the GG genotype at rs872129 specifically elevates or lowers the YKL-40 setpoint (versus the alternative that it disrupts normal YKL-40 regulation in a direction-indeterminate way) remains to be established definitively.