Multiple Loci within the Major Histocompatibility Complex Confer Risk of Psoriasis

Abstract

Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2×10 ⁻⁶, OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9×10 ⁻⁶, OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3×10 ⁻⁴⁷, 6×10 ⁻⁸, and 3×10 ⁻⁷, respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.

Author Summary

Psoriasis (Ps) is a chronic inflammatory disease of the skin, affecting approximately 2% of Europeans. The HLA-C gene, located within the major histocompatibility complex (MHC) region on chromosome 6, is the major genetic determinant of psoriasis. However, multiple susceptibility genes within MHC are also hypothesized. Recently, we carried out a genome-wide association scan (GWAS) on psoriasis with 1,359 patients and 1,400 healthy controls, which identified seven psoriasis loci in the human genome and confirmed the effect of HLA-C. This dataset contains densely distributed genetic variations, single nucleotide polymorphisms (SNPs), which were then further analyzed in search for additional susceptibility genes within the MHC region. Using the SNP data, we imputed in all samples the HLA-C risk allele with high accuracy. Adjusting for the HLA-C, two additional loci, one near C6orf10 and one near HLA-B/MICA, have significant associations with psoriasis, which were also observed in an independent Han Chinese dataset, suggesting that within the MHC there are at least three genes moderating susceptibility to psoriasis.