rs187080438 — CTSS Cathepsin S antigen presentation variant

CTSS — The Immune Protease Behind Atopic Dermatitis Risk

Cathepsin S (CTSS) is a lysosomal cysteine protease with an indispensable role at the heart of adaptive immunity: it is the primary enzyme that cleaves the invariant chain (Ii/CD74) from MHC class II molecules¹¹ MHC class II molecules
MHC class II is the cellular machinery that presents antigens to CD4+ T helper cells, initiating and shaping immune responses, enabling antigen loading and T-cell activation. When CTSS function is altered — whether by genetic variation or pathological upregulation — the cascade of T-cell priming and inflammatory cytokine production shifts in ways that promote atopic disease. This variant in the CTSS locus was identified as a novel atopic dermatitis risk locus in a large GWAS meta-analysis, underscoring a fundamentally immunological origin for eczema susceptibility.

The Mechanism

In professional antigen-presenting cells (dendritic cells, B cells, and macrophages), CTSS is the rate-limiting protease for removing the invariant chain from MHC class II molecules inside endosomes. Without efficient CTSS activity, peptide loading onto MHC class II is impaired; with excess CTSS activity, antigen presentation is amplified and self-tolerance can break down. Cathepsin S-deficient mice accumulate Ii-MHC II complexes and show severely impaired CD4+ T-cell responses²² Cathepsin S-deficient mice accumulate Ii-MHC II complexes and show severely impaired CD4+ T-cell responses
Riese et al. demonstrated that specific cathepsin S inhibition in B lymphoblastoid cells prevented complete proteolysis of the invariant chain and blocked SDS-stable peptide-loaded complexes.

Beyond its role in classical antigen presentation, CTSS is also secreted extracellularly by skin-resident dendritic cells and keratinocytes, where it activates proteinase-activated receptor 2 (PAR2)³³ activates proteinase-activated receptor 2 (PAR2)
PAR2 activation by CTSS triggers downstream TRPV1 signaling in sensory neurons on sensory nerve endings — directly triggering itch. This dual role in both antigen presentation and pruritus makes CTSS a mechanistically coherent risk gene for atopic dermatitis, which is defined by both immune dysregulation and chronic itch.

The rs187080438 T allele is an intronic variant in the flanking RPRD2 gene approximately 328 kb upstream of CTSS on chromosome 1q21. Although the variant itself does not alter any CTSS protein residue, GWAS loci routinely act through cis-eQTL mechanisms⁴⁴ cis-eQTL mechanisms
expression quantitative trait loci regulate the level of nearby gene transcription in a tissue-specific manner, commonly in immune cell types that alter gene expression levels, particularly in the immune cell types where CTSS is most active. The full mechanistic link between this specific intronic variant and CTSS expression changes in human immune cells awaits functional follow-up.

The Evidence

Budu-Aggrey et al. (2023, Nature Communications)⁵⁵ Budu-Aggrey et al. (2023, Nature Communications)
European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation. Nat Commun. 2023;14(1):6280 conducted a GWAS meta-analysis including 65,107 atopic dermatitis cases and 1,021,287 controls in the European discovery phase, plus a multi-ancestry expansion to 765,209 individuals. Rs187080438 emerged as one of 29 novel loci genome-wide (OR=1.17, 95% CI 1.11–1.23, p=3.7×10⁻¹⁰). The finding replicated robustly in an independent 23andMe European cohort of 2,904,664 individuals (OR=1.14, p=2.0×10⁻⁴¹), making false-positive inflation highly unlikely. The CTSS gene was nominated as the most biologically plausible candidate given its tissue expression profile and established role in immune regulation.

The animal model evidence is compelling: Kim et al. (2012)⁶⁶ Kim et al. (2012)
Overexpression of cathepsin S induces chronic atopic dermatitis in mice. J Invest Dermatol. 2012;132(4):1169–76 showed that CTSS-overexpressing transgenic mice spontaneously develop a chronic atopic dermatitis-like skin disorder with PAR-2 upregulation, scratching behavior, and altered T-helper cytokine profiles. Separately, Chung et al. (2019)⁷⁷ Chung et al. (2019)
Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour. Neurobiol Pain. 2019 established the itch pathway: injected human recombinant CTSS caused dose-dependent scratching in mice that was abolished by PAR2 antagonists and reduced 50% in TRPV1-knockout mice. This convergent evidence — GWAS signal, transgenic mouse model, mechanistic itch pathway — places CTSS among the more biologically grounded novel AD loci. The evidence level is rated moderate: the GWAS association is well-powered and replicated, but functional confirmation of rs187080438's effect on CTSS expression in human tissue is not yet published.

Practical Actions

The T allele is present in roughly 2–3% of Europeans and is extremely rare in East Asian and African populations, indicating this locus contributes primarily to AD risk in European-ancestry individuals. For carriers, the OR of 1.17 represents a modest but statistically robust elevation in atopic dermatitis risk.

Because the biological mechanism is CTSS-mediated antigen dysregulation and PAR2-driven itch, practical management focuses on reducing the downstream consequences: attenuating type 2 immune skewing, protecting the skin barrier to limit the antigen challenge that CTSS amplifies, and addressing the PAR2-itch axis. Emollient therapy that maintains barrier integrity reduces the antigen load reaching dendritic cells and thus the antigen-presentation amplification that elevated CTSS activity drives.

Serine/cysteine protease inhibitors targeting CTSS are under active investigation as therapeutic targets for atopic dermatitis and asthma — carriers of this locus may be particularly responsive to this class of emerging therapies.

Interactions

Two additional CTSS-region variants (rs146527530 and rs115161931) were identified as independent signals in the same GWAS meta-analysis, at positions 151,059,196 and 151,063,299 (GRCh38) with ORs of 1.27 and 1.18 respectively. These may reflect distinct regulatory mechanisms acting on CTSS or on nearby genes. Co-occurrence of multiple CTSS-locus risk alleles could compound individual risk; compound action evidence across these variants has not yet been formally studied.

Within the broader AD genetic architecture, CTSS operates downstream of the epithelial barrier (FLG, SPINK5, KIF3A) and upstream of adaptive immune polarization (STAT6, IL13, IL4). Individuals with both barrier-gene defects and CTSS-locus risk may face an amplified antigen-presentation burden, as more antigens penetrate the defective barrier and encounter a sensitized CTSS-driven presentation pathway.