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=210 6 , OR=0.66), located within c6orf10 , a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p=910 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=310 47 , 610 8 , and 310 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.

... 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=210 6 , OR=0.66), located within c6orf10 , a potential downstream effecter of TNF

... 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

... 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. Introduction Psoriasis (Ps) is

... dataset; (C) Logistic regression adjusted for HLA-Cw*0602 and rs2073048 in the GAIN dataset. (D) Logistic regression adjusted for HLA-Cw*0602 in the Chinese dataset; (E) Logistic regression adjusted for HLA-Cw*0602 and rs28732201 in the Chinese dataset. The red lines indicate the significance level by Bonferroni correction for the number of SNPs tested. The numbers of SNPs are 1593, 1593, 1591, 226, and 252 for (AE), respectively. C6orf10 is associated with psoriasis To examine the association of

... significantly associated with Ps after adjustment for HLA-Cw*0602 . However, as seen in Figure 1B , we observed other SNPs that remained significant after Bonferroni correction for multiple testing. The SNP exhibiting the highest significance level, rs2073048, is located at position 32.4 Mb within an open reading frame, C6orf10 , 27 kb telomeric to BTNL2 and 144 kb centromeric to NOTCH4 . The minor allele (G) at this SNP had a frequency of 15% in controls and was associated with an adjusted odds ratio of

... risk of psoriasis (OR=1.32 [1.171.49], p=910 6 ). In analyses adjusted for HLA-Cw*0602 and rs2073048 ( Figure 1C ), the association of this SNP was even stronger (OR=1.38 [1.221.57], p=310 7 ), suggesting that the observed association is not due to the LD with HLA-C or C6orf10 . In stratified analyses, there was no evidence of heterogeneity when samples were stratified by HLA-Cw*0602 , rs2073048, or both (p=0.21, 0.26, and 0.58, respectively), showing that the association of this locus is independent of HLA-C and of the C6orf10 locus. When both of the newly identified putative susceptibility loci and HLA-Cw*0602 were included in a logistic regression model, each of them was significantly associated with disease (p=310 47 , 610 8 and 310 7 , for HLA-Cw*0602 , rs2073048 and rs13437088, respectively). Individuals carrying risk genotypes at HLA-C , rs2073048 and rs13437088 were estimated to be at a nine-fold increased risk of psoriasis compared to those carrying low risk genotypes at all three

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Gene: C6orf10 - chromosome 6 open reading frame 10 - (NCBI)

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