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.

Fine mapping of eight psoriasis susceptibility loci

“…This differential association has been suggested previously, albeit in much smaller studies, 10,12,33 but to our knowledge this is the first time the difference in strength of association has been shown to be statistically significant.…”

“…Although the primary signals agree with each other, the conditional signals of similar rank are not in high LD with each other. Our secondary signal (rs6924962) exhibits moderate LD with the fifth signal rs66609536 chr6.hg19.g.31362120G4A (r 2 ¼ 0.56) in Knight et al 8 and the third signal rs13437088 chr6.hg19.g.31355119T4C (r 2 ¼ 0.56) in Feng et al 12 We identified the same variant near IL13 (rs1295685) that was identified in the GWAS-Immunochip meta-analysis, and our primary signals in TNIP1 (rs17728338), TNFAIP3 (rs642627) and IL12B (rs62377586) are in strong LD with the top markers for each locus in that analysis (rs2233278 chr5.hg19.g.150467189C4G (r 2 ¼ 0.96), rs582757 chr6.hg19.g.138197824A4G (r 2 ¼ 0.97) and rs4379175 Fine mapping of eight psoriasis susceptibility loci S Das et al Fine mapping of eight psoriasis susceptibility loci S Das et al chr5.hg19.g.158804928G4T (r 2 ¼ 0.84), respectively). The signal at rs61937678 in the IL23A region is in physical proximity (B96.51 kb) of the signal detected at rs2066819 chr12.hg19.g.56750204G4A in the meta-analysis, although the LD between these two SNPs is nominal (r 2 ¼ 0.2).…”

“…Our results for the MHC region provide a completely independent replication of two previous fine-mapping studies of this same region. 8,12 Although the primary signals agree with each other across all three studies, the conditional signals of similar rank are not in high LD with each other. Our third signal from MHC (rs892666) does not exhibit high LD with any previously identified MHC signal, but lies only 7.8 kb from the fourth signal of Knight et al 8 study.…”

“…We also compared our results for the MHC region with other finemapping studies of the same region 8,12 (Figure 4). Although the primary signals agree with each other, the conditional signals of similar rank are not in high LD with each other.…”

“…Previous fine-mapping studies in psoriasis have focused on the MHC, helping localize the primary risk locus 10,11 and identify multiple psoriasis susceptibility alleles. 8,12 Using a combination of genotyping and imputation, 13 we examined in detail the genetic variation in each of the eight psoriasis susceptibility regions (MHC, IL12B, IL23A, IL23R, TNIP1, TNFAIP3, IL13 and RNF114) in a large sample of subjects of European ancestry, over 97% of whom were not previously subjected to fine-mapping. We sought to identify the variant with strongest association in each locus as well as to find out whether multiple variants might be independently associated in the same locus.…”