Dataset Information

A Large-Scale, Stratified Genetic Analysis of the Major Histocompatibility Complex Region in Early- and Late-Onset Psoriasis in China.

ABSTRACT:

Background

Psoriasis vulgaris is a chronic inflammatory skin disease which occur at any age. It can be clinically classified into two age-onset subtypes: early-onset psoriasis (EOP; <40 years) and late-onset psoriasis (LOP; ≥40 years). More evidence showed EOP and LOP have different genetic architecture, notably the risk allele human leukocyte antigen (HLA)-C^*06:02 located within the major histocompatibility complex (MHC) region, which was reported to be the outstanding variant associated with EOP. However, genetic structure of EOP and LOP have not been fully elucidated.

Objective

To investigated HLA genetic heterogeneity between EOP and LOP in China.

Methods

We first calculated the MHC-based heritability of EOP and LOP respectively. Then, we conducted a large-scale, stratified analysis including 7,097 EOP, 1,337 LOP patients, and 9,906 healthy controls by using MHC target sequencing data from a previous study.

Results

We observed that HLA alleles collectively explained a larger heritability of EOP (27.4%) than LOP (11.3%). Further association analysis identified three independent loci (HLA-C^*01:02, p=6.70×10^-8; HLA-A amino acid position 9, p=3.27×10^-17; and HLA-A amino acid position 161, p=5.75×10^-10) that confer specific susceptibility to EOP. Our data also confirmed HLA-C^*06:02 as an independent psoriasis-associated variant, contributing a higher degree of risk to EOP than LOP. Moreover, case-case analysis confirmed that HLA-C^*06:02-positive psoriasis patients have earlier onset.

Conclusion

Our analysis indicating that different genetic background underlie the EOP and LOP. We believe these findings will serve to predict psoriasis risk in the future and facilitate clinical decision.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC7875217 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 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 x 10(-47), 6 x 10(-8), and 3 x 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.