Session Title: Genetics and Genomics of Rheumatic Disease II
Session Type: Abstract Submissions (ACR)
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.
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.
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).
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.
D. D. Gladman,
« Back to 2013 ACR/ARHP Annual Meeting
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/