Background/Purpose:

We previously reported associations between alleles of the major histocompatibility complex class I chain-related gene A (MICA) and psoriatic disease that were independent of HLA-B despite their tight linkage disequilibrium. In a larger cohort of patients, we sought to investigate the association with MICAalleles and determine if associations are evident at the amino acid level.

Methods:

Caucasian psoriatic disease patients [786 PsA patients satisfying CASPAR criteria and 358 psoriasis patients without arthritis (PsC)], and 717 unaffected controls were recruited from a large cohort. MICA and HLA-B allelic typing was performed by PCR-SSO. Univariate logistic regressions were performed using MICA and HLA-B alleles as predictor variables for psoriatic disease compared to controls, and PsA compared to PsC. Multivariate logistic regressions used significant MICA alleles with significant HLA-B alleles as covariates. MICA-HLA-B haplotypes were estimated using the EM algorithm and differences between subject groups were analyzed using SNP & Variation Suite 7 software. MICAalleles were converted into amino acids at each polymorphic site of the mature MICA protein and analyzed for differences between groups.

Results:

PsA patients were 58% male, mean age (s.d.) at diagnosis of psoriasis 28 (14.4) years, age at PsA diagnosis 36 (13.0) years, and PASI 5.3 (8.1). Psoriasis patients were 55% male, mean age at diagnosis of psoriasis 30 (16.6) years, and PASI 5.3 (4.9). Controls were 43% male. MICA*002:01, *004, *007:01, *008:01, *009:01, *010:01, *016, *017, and *027 were associated with psoriatic disease compared to controls, and MICA*007:01 and *017 were associated with PsA compared to PsC in univariate analyses (p<0.05). After adjusting for HLA-B alleles, only MICA*016 was independently associated with psoriatic disease (OR=2.1, p<0.01), and MICA*007:01 with PsA (OR=3.2, p=0.04). Haplotypes MICA*016-B*3501 (OR=3.2, p<0.01), MICA*017-B*5701 (OR=2.5, p<0.01) and MICA*002:01-B*3801 (OR=6.5, p<0.01) were among those increased in psoriatic disease compared to controls. Haplotype MICA*007:01-B*2705 (OR=4.1, p<0.01) was increased in PsA compared to PsC, while haplotypes MICA*017-B*5701 (OR=0.54, p<0.01) and MICA*008:01-B*1302 (OR=0.42, p<0.01) were decreased. Methionine at amino acid position 129 (M129), which is present in MICA*002:01, *007:01 and *017, was associated with psoriatic disease compared to controls (OR=1.9, p<0.01), and was strongly associated with amino acids G206, W210, S215, C36, and K173. Arginine at position 91 (R91), which is unique to MICA*017, was decreased in PsA compared with psoriasis patients (OR=0.57, p<0.01).

Conclusion:

We confirmed the HLA-B-independent association of MICA*016 with psoriatic disease, and found a new association between MICA*007:01 and PsA. MICA alleles containing the M129 amino acid are associated with psoriatic disease, while the MICA*017 allele containing the R91 amino acid are protective against PsA in psoriasis patients. Further genetic and structural studies are needed to understand the significance of these findings.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-alleles-and-amino-acids-of-the-major-histocompatibility-complex-class-i-chain-related-gene-a-with-psoriatic-disease/