rs2469434 — CD226

Deep-intronic variant in the CD226 (DNAM-1) co-stimulatory receptor gene associated with rheumatoid arthritis, multiple sclerosis, and altered neutrophil and white blood cell counts, likely acting as a regulatory variant that modulates CD226 expression in immune cells

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CD226 Intronic Variant — A Regulatory Signal at the DNAM-1 Autoimmune Locus

CD226 (also known as DNAM-1, DNAX Accessory Molecule-1)11 CD226 (also known as DNAM-1, DNAX Accessory Molecule-1)
A co-stimulatory receptor expressed on T cells, natural killer cells, and myeloid cells that delivers activating signals when it binds PVR (CD155) or Nectin-2 (CD112) on antigen-presenting cells and stressed tissues is one of the few genes in the human genome where both coding and non-coding genetic variation independently contribute to autoimmune risk. rs2469434 sits deep within an intron of CD226 on chromosome 18q22, roughly 12,000 base pairs from the functionally well-characterised coding variant rs763361 (Gly307Ser). The two variants capture distinct signals at the same locus: rs763361 changes the protein's cytoplasmic signalling domain, while rs2469434 is thought to act through regulatory mechanisms — altering CD226 expression levels in immune cells rather than protein structure.

The Mechanism

rs2469434 maps to the notation c.728-3564 in the canonical CD226 transcript (NM_006566.4), placing it 3,564 nucleotides upstream of a major exon boundary — far from splice sites and beyond the reach of conventional splicing effects. The most plausible functional interpretation is that this variant lies within an intronic enhancer or silencer element22 enhancer or silencer element
Regulatory DNA sequences within introns that bind transcription factors and modulate gene expression levels without altering the protein sequence, modulating CD226 transcription in immune cell types. The GWAS signal for altered neutrophil count and total white blood cell count — two haematopoietic phenotypes with high expression in circulating immune cells — is consistent with a cis-regulatory effect on CD226 expression during immune cell maturation and differentiation.

CD226 itself delivers co-stimulatory signals that lower the activation threshold of both innate NK cells and adaptive T cells. Higher expression of the receptor (or dysregulated expression timing) translates into lower thresholds for immune cell activation — the cellular substrate for autoimmune tissue damage. The C risk allele at rs2469434 is associated with increased neutrophil count and elevated WBC in the largest multi-ethnic blood cell GWAS to date (Chen MH et al. 2020, 746,667 individuals)33 (Chen MH et al. 2020, 746,667 individuals), consistent with a CD226 regulatory effect on myeloid cell development or survival.

The Evidence

The rheumatoid arthritis association at rs2469434 was established by the landmark Okada et al. 2014 RA GWAS meta-analysis44 Okada et al. 2014 RA GWAS meta-analysis
Okada Y et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 2014; >100,000 subjects, 29,880 RA cases, 73,758 controls, which mapped 42 novel RA risk loci including the CD226 18q22 region. The C allele shows an odds ratio of approximately 1.07 (95% CI 1.05–1.10) in European populations and 1.11 (95% CI 1.07–1.15) in East Asian populations, with genome-wide significance (P=9×10⁻¹⁰ and 1×10⁻⁸ respectively). These effect sizes are modest — consistent with the polygenic architecture of RA, where each individual variant contributes a small increment to cumulative risk.

The multiple sclerosis association comes from the International MS Genetics Consortium 2019 study55 International MS Genetics Consortium 2019 study
Published in Science, 47,429 MS cases and 68,374 controls; established 200 autosomal susceptibility variants outside the MHC, which found rs2469434-C associated with MS susceptibility at OR 1.055 (P=3×10⁻⁸).

Importantly, the haematopoietic phenotype associations — neutrophil count (P=10⁻¹⁶) and total WBC count (P=5×10⁻¹³) from Chen MH et al. 2020 — provide mechanistic support for the autoimmune risk associations. Both phenotypes are cellular traits with well-known links to immune activation and autoimmune disease activity: elevated neutrophil counts are observed in active RA and MS flares, and circulating neutrophil levels are an intermediate phenotype between CD226 regulatory variants and clinical autoimmune disease expression.

Practical Implications

The per-allele ORs from this intronic variant (1.07–1.11 for RA, 1.055 for MS) are modest but real, and they act independently of the better-characterised rs763361 (Gly307Ser) coding variant. For CC homozygotes carrying two C alleles, the cumulative effect is approximately the square of the per-allele OR — roughly 1.14–1.23 × the risk of TT homozygotes, depending on the disease. In the context of RA and MS, which are both T-cell-mediated diseases with well-defined early biomarkers, monitoring for early signs is the primary actionable response.

Interactions

rs2469434 and rs763361 both map to the CD226 locus and independently associate with overlapping autoimmune diseases. Their independence as signals means a person can carry risk alleles at both variants, producing a compound effect at the CD226 locus beyond what either variant predicts alone. More broadly, the CD226 18q22 locus interacts pathogenically with other T-cell checkpoint genes: PTPN22 rs2476601 (LYP phosphatase), CTLA4 rs3087243 and rs231775 (inhibitory co-receptor), and IL2RA rs2104286 (IL-2 receptor alpha). All four genes converge on the T-cell activation/tolerance decision, and elevated CD226 expression from rs2469434 would amplify the effect of any co-existing checkpoint gene risk alleles.

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal

Homozygous reference — baseline CD226 locus autoimmune risk

You carry two copies of the T (reference) allele at rs2469434 in the CD226 gene. This genotype is associated with typical CD226 expression levels and background risk for CD226-associated autoimmune diseases. Approximately 32% of people globally share this genotype. Your risk for rheumatoid arthritis and multiple sclerosis from this particular variant is at or below the population average.

CT Intermediate

One C allele — modestly elevated CD226 locus autoimmune risk

rs2469434 is an intronic variant in CD226 thought to modulate expression of the co-stimulatory receptor DNAM-1. A single C allele is associated with modest shifts in neutrophil and white blood cell counts in population studies, consistent with altered CD226 expression during immune cell differentiation. At the disease level, the per-allele OR for RA (~1.07–1.11) and MS (~1.055) is additive — carrying one copy contributes approximately half the cumulative risk shift of two copies.

This variant operates independently of the better-known CD226 missense variant rs763361 (Gly307Ser). If you also carry risk alleles at rs763361, the two CD226 signals compound each other at the same locus, and the combined risk at this gene is higher than either variant predicts alone.

CC High Risk

Two C alleles — elevated CD226 locus risk for RA and MS

The CC genotype at rs2469434 places both copies of the CD226 regulatory element in the risk configuration, likely resulting in consistently altered CD226 expression across immune cell types. The haematopoietic phenotype associations (neutrophil count P=10⁻¹⁶, WBC count P=5×10⁻¹³) confirm that this variant has a biologically measurable effect on immune cell profiles even in healthy individuals, not just in people with diagnosed autoimmune disease.

In the context of RA, the CD226 18q22 locus including rs2469434 was identified in the Okada et al. 2014 Nature GWAS (29,880 RA cases, 73,758 controls) as one of 101 RA risk loci, with genome-wide significance in both European and East Asian populations. The East Asian signal is slightly stronger (OR 1.11 vs 1.07), consistent with the documented differences in CD226 locus architecture across populations.

CC homozygosity at this intronic regulatory variant is most actionable when combined with a check of the coding variant rs763361 — someone with CC at rs2469434 and TT at rs763361 carries risk signals from two independent functional elements in the same gene.