rs4406273 — HLA-C

HLA-C*06:02 — The Master Psoriasis Susceptibility Haplotype

The HLA-C gene sits at the heart of the immune system's antigen presentation machinery, producing the HLA-C protein that displays peptide fragments to CD8+ cytotoxic T cells¹¹ CD8+ cytotoxic T cells
MHC class I molecules present endogenous peptides to CD8+ T cells, enabling immune surveillance of cellular protein content. One particular version of this protein — encoded by the HLA-C*06:02 haplotype — is the strongest single genetic risk factor for psoriasis, accounting for the largest fraction of genetic predisposition²² the largest fraction of genetic predisposition
HLA-C*06:02 on PSORS1 is the primary psoriasis susceptibility allele in Caucasian populations, responsible for a large fraction of familial risk to early-onset disease in European populations. The SNP rs4406273, located approximately 28.7 kb upstream of HLA-C, acts as a near-perfect proxy for the HLA-C*06:02 allele — across European, South Asian, and Southeast Asian cohorts, genotype concordance is 0.984–0.996 (r²=0.946–0.984), making this single SNP almost as informative as full HLA typing.

The Mechanism

HLA-C*06:02 drives psoriasis through a specific autoimmune pathway targeting skin melanocytes. The critical autoantigen is ADAMTS-like protein 5 (ADAMTSL5)³³ ADAMTS-like protein 5 (ADAMTSL5)
ADAMTSL5 is highly expressed in psoriasis lesions, especially in melanocytes; ADAMTSL5-specific CD8+ T cells are detectable in patients and produce IL-17A, a peptide that HLA-C*06:02 presents to skin-infiltrating CD8+ T cells. These T cells produce the pathogenic cytokine IL-17A⁴⁴ IL-17A
IL-17A stimulation of keratinocytes drives the epidermal hyperproliferation that produces psoriatic plaques, which drives keratinocyte hyperproliferation and the characteristic plaques of psoriasis vulgaris. Carriers of HLA-C*06:02 have odds ratios for psoriasis ranging from 3.4 to 4.9 depending on the population studied.

The interaction with ERAP1 (endoplasmic reticulum aminopeptidase 1) reveals an elegant molecular specificity: ERAP1 trims peptide precursors⁵⁵ trims peptide precursors
ERAP1 acts as a gatekeeper, trimming NH2-terminal extended precursors to the exact peptide length required for HLA-C*06:02 binding and presentation to the optimal size for HLA-C*06:02 binding. Different ERAP1 haplotypes produce different amounts of the ADAMTSL5 autoantigen, meaning ERAP1 variants only influence psoriasis risk in HLA-C*06:02 carriers⁶⁶ ERAP1 variants only influence psoriasis risk in HLA-C*06:02 carriers
ERAP1 variants confer risk only in individuals with the HLA-C risk allele; no effect in non-carriers, establishing HLA-C as a prerequisite for ERAP1-mediated risk — an example of genetic epistasis where the effect of one gene depends entirely on the context of another.

The Evidence

The landmark psoriasis GWAS by Strange et al. 2010⁷⁷ The landmark psoriasis GWAS by Strange et al. 2010
Large multi-cohort GWAS identifying new psoriasis loci including the HLA-C × ERAP1 epistatic interaction, P_combined=6.95×10−6 established the HLA-C/ERAP1 interaction and confirmed HLA-C as the primary PSORS1 signal. Stuart et al. 2015 validated rs4406273⁸⁸ Stuart et al. 2015 validated rs4406273
Genotype concordance 0.984–0.996; sensitivity 0.965–1.000; specificity 0.9963–0.9994 as a surrogate for HLA-C*06:02 across European, Asian, and some African and admixed populations as an excellent single-SNP surrogate across multiple diverse cohorts, reporting ORs of 3.38, 2.32, and 4.91 in Michigan, Pakistani, and Thai samples respectively.

HLA-C*06:02 status has emerged as a clinically useful predictive biomarker⁹⁹ clinically useful predictive biomarker
Meta-analysis (937 patients at 6-month timepoint); risk difference of 0.24 (95% CI 0.14–0.35, P<0.001) in PASI75 response favoring HLA-C*06:02-positive patients on ustekinumab for biologic drug response in psoriasis. HLA-C*06:02-positive patients achieve substantially higher response rates on ustekinumab (anti-IL-12/IL-23) — approximately 89–92% achieving PASI75 at 6 months versus 62–67% in HLA-C*06:02-negative patients.

Phenotypically, HLA-C*06:02-positive patients are more likely to present with guttate lesions, greater body surface area, and higher PASI scores¹⁰¹⁰ guttate lesions, greater body surface area, and higher PASI scores
HLA-Cw6 positivity associated with guttate psoriasis, greater body surface area, and higher PASI scores in multiple cohorts and earlier disease onset (type I psoriasis, onset before age 40).

Practical Actions

HLA-C*06:02 carrier status (tagged by rs4406273-A) has direct, genotype-specific clinical implications. If you carry one or two copies of the A allele, your dermatologist should be informed: this genotype predicts better response to ustekinumab (Stelara) and poorer relative benefit from some other biologics. It also warrants heightened awareness of early psoriasis symptoms — particularly following streptococcal throat infections, which are a known trigger for guttate flares specifically in HLA-C*06:02 carriers.

Homozygous AA carriers face substantially elevated risk and should establish regular dermatological follow-up even without current disease, since psoriasis is often preceded by subclinical immune activation. Triggers known to unmask or exacerbate psoriasis in HLA-C*06:02 carriers include streptococcal infections, stress, skin trauma (Koebner phenomenon), and certain medications (lithium, beta-blockers).

Interactions

The most important interaction is with ERAP1 (rs27524). ERAP1 risk alleles only increase psoriasis susceptibility in individuals who also carry the HLA-C risk allele. A user carrying risk alleles at both rs4406273 (HLA-C*06:02 proxy) and rs27524 (ERAP1) has a substantially higher combined risk than either variant alone, because ERAP1 controls the generation of the very autoantigen that HLA-C*06:02 presents to pathogenic T cells.

The related SNP rs12191877 is another HLA-C*06:02 tagging SNP at a different position; both co-segregate with the same HLA-Cw6 haplotype and share near-identical psoriasis associations. They provide complementary coverage for HLA-C*06:02 detection rather than marking independent biological signals.