rs10484554 (HLA-C): Psoriasis Susceptibility Variant

Key takeaways

• Located in the MHC class I region on chromosome 6p21, near HLA-C, the most studied genetic risk zone for psoriasis
• Homozygous carriers have roughly 10-fold higher psoriasis odds, making this one of the largest effect sizes documented for any common disease
• Linked to both skin-limited psoriasis and psoriatic arthritis, with the MHC signal possibly stronger for skin disease
• The alternate allele increases expression of nearby immune genes HLA-S and PSORS1C2 in blood, lung, and other tissues
• A nearby HLA-B region variant (rs2395029) is separately linked to HIV nonprogression but is independent of rs10484554

What the research says rs10484554 maps to the chromosome 6p21 Major Histocompatibility Complex (MHC - the stretch of DNA encoding many immune proteins) class I region, approximately 34.7 kb upstream from HLA-C, the primary candidate gene for the psoriasis susceptibility locus known as PSORS1 PMID 18846228. In a GWAS (genome-wide association study) of 2,622 psoriatic individuals and 5,667 controls, this variant was the top association signal in the region (P = 4 × 10^-²¹^4, OR = 4.66, 95% CI: 4.23-5.13), with heterozygotes (one copy of the risk allele) showing an OR of 5.41 and homozygotes (two copies) an OR of 10.61, a pattern inconsistent with a simple per-allele genetic model PMID 20711174. A second study in independent U.S. and U.K. cohorts confirmed the association (combined P = 1.8 × 10^-³^9) and found a significant signal for psoriatic arthritis as well (P = 6.9 × 10^-¹¹ in a U.K. PSA cohort) PMID 18846228.

Reported associations

• Psoriasis vulgaris: Top MHC class I GWAS signal; OR = 4.66 (95% CI: 4.23-5.13) per allele; heterozygote OR = 5.41 (95% CI: 4.81-6.08); homozygote OR = 10.61 (95% CI: 7.86-14.33); P = 4 × 10^-²¹^4; discovery cohort of 2,622 cases and 5,667 controls PMID 20711174
• Psoriasis vulgaris (replication): GWA scan P = 7.8 × 10^-¹¹; combined P = 1.8 × 10^-³^9 across discovery and independent replication cohorts (577 U.S. cases, 737 controls; 576 U.K. PSA cases, 480 controls); variant lies 34.7 kb upstream from HLA-C PMID 18846228
• Psoriatic arthritis (PSA): Significant MHC class I association in a U.K. PSA cohort (P = 6.9 × 10^-¹¹) PMID 18846228
• Cutaneous psoriasis vs. PSA differential: A meta-analysis totaling 9,293 psoriasis vulgaris cases (including 3,061 PSA) and 13,670 controls found a nearby HLA-C variant (rs12189871) more strongly associated with skin-limited psoriasis than with PSA (P = 5.0 × 10^-¹^9), suggesting MHC class I variants preferentially drive cutaneous disease PMID 27132596

Evidence quality The association between rs10484554 and psoriasis is among the most robustly replicated in common-disease genetics. A discovery GWAS of 2,622 cases and 5,667 controls yielded P = 4 × 10^-²¹^4 PMID 20711174, and an independent replication study confirmed the signal with a combined P = 1.8 × 10^-³^9 PMID 18846228. Evidence for a non-multiplicative (roughly dominant) inheritance pattern was also reported, with a statistically significant departure from a per-allele model (P = 1.95 × 10^-8) and heterozygote and homozygote ORs both substantially higher than a linear model predicts PMID 20711174. A multi-cohort meta-analysis of 9,293 psoriasis cases and 13,670 controls further confirmed the MHC class I region as the dominant psoriasis genetic signal and began resolving it into variants with differing relative strength for cutaneous versus arthritic disease subtypes PMID 27132596. Research also found compelling evidence that ERAP1 (Endoplasmic Reticulum Aminopeptidase 1 - a protein that prepares peptides for display by MHC class I molecules) interacts with the HLA-C risk allele: ERAP1 variants influenced psoriasis susceptibility only in carriers of the HLA-C risk allele (Pcombined = 6.95 × 10^-6) PMID 20711174. No conflicting findings have been reported for rs10484554 as a psoriasis risk variant. A nearby variant in the HCP5 gene (rs2395029), which is in linkage disequilibrium (genetically correlated) with HLA-B and has been associated with HIV-1 disease nonprogression (OR = 3.47, P = 6.79 × 10^-¹^0) PMID 19493101, exerts a psoriasis effect that is independent of rs10484554 PMID 18846228.

Tissue-specific expression effects

• HLA-S: The rs10484554 alternate allele is associated with increased expression of HLA-S (an MHC class I gene) across immune-relevant tissues, most strongly in whole blood and lung, and also in visceral and subcutaneous adipose tissue GTEx Portal
• PSORS1C2: The same allele is associated with increased expression of PSORS1C2 (Psoriasis Susceptibility 1 Candidate 2) in sigmoid colon, thyroid, lung, and esophageal muscularis tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.