Variation in EraP Influencees Risk for HLA-B*57:01 positive abacavir hypersensitivity

R. Pavlos; K. Strautins; I. James; S. Mallal; A.J. Redwood; E. Phillips

Abacavir (ABC) binds non-covalently to the floor of the peptide-binding groove of HLA-B*57:01, altering the chemistry and shape of the antigen binding cleft. This allows previously untolerized self-peptides to be presented by HLA-B*57:01 which upon T-cell receptor binding initiates a CD8+ T-cell response and a clinical hypersensitivity reaction(HSR). Endoplasmic reticulum aminopeptidases (ERAPs) trim peptides for MHC Class I presentation, influencing the degree and specificity of the CD8+ T-cell response. Genetic variation within ERAP adds to the positive predictive value (PPV) of the HLA class I risk allele in autoimmune diseases such as HLA-B27 positive ankylosing spondylitis. Considering the altered peptide repertoire mechanism of ABC HSR we hypothesize that variation in ERAP may help explain why 45% carrying HLA-B*57:01 can tolerate ABC. SNPs within ERAP1 (rs27044, rs17482078, rs30187, rs27434, rs2287987) were examined in HLA-B*57:01+ ABC HSR patch test positive (PT+)[n=53] and HLA-B*57:01+ ABC tolerant[n=22] with sequence-based typing. Rs2248374, a tag SNP for functional ERAP2 haplotypes was also examined. Haplotype A is tagged by the (A) allele, while haplotype B is tagged by rs2248374(G). Fisher exact tests and multiple logistic regressions were used to compare genotypes between the ABC HSR PT+ and tolerant groups. HLA-B*57:01+ ABC tolerance was associated with rs27434(GG) (18/22(82%) vs 24/53(45%) in ABC HSR PT+, p=0.005). This SNP maps to the active site within ERAP1 (AA356). For an HLA-B*57:01 positive population the estimated PPV for rs27434 genotypes for ABC HSR PT+ is AA(100%), AG(77%) and GG(40%). A missense mutation within the domain junction (rs30187(C)) important in conformation change of ERAP1 (AA528), was overrepresented in HLA-B*57:01+ ABC tolerant individuals (p=0.04). Analysis indicated linkage between rs27044 and rs30187, rs17482078 and rs2287987, and between rs30187 and rs27434 (all p < 0.0001). In a multivariable model with rs27434(GG), the ERAP2 SNP (rs2248372(G)) that tags haplotype B which is characterized by a truncated protein, was decreased in tolerant individuals (p = 0.005). ERAP and particularly ERAP1 variants are important in the development of ABC HSR. ERAP activity may influence the repertoire of peptides presented by HLA-B*57:01 or influence early changes in immunodominant epitope selection. This provides a potential pathogenic mechanism for the development of ABC HSR or ABC tolerance in HLA-B*57:01 carriers.

Variation in EraP Influencees Risk for HLA-B*57:01 positive abacavir hypersensitivity

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