Mapping of genetic susceptibility to abacavir hypersensitivity
Martin, A., Gaudieri, S., Witt, C., Nolan, D., Christiansen, F.T. and Mallal, S. (2003) Mapping of genetic susceptibility to abacavir hypersensitivity. In: 10th Conference on Retroviruses and Opportunistic Infections, 10 - 14 February 2003, Boston, U.S.A.
Background: Hypersensitivity reactions to abacavir, a nucleoside analogue, occurs in 5% of treated patients (pts). This sometimes lethal reaction occurs within 6 wks of exposure and rapidly recurs with increased severity on re-challenge. It has been proposed that pts may be predisposed to such reactions by genetic polymorphisms. Likely candidate genes are those involved in the metabolism of the drug or MHC-restricted immune responses. We have previously shown the presence of the 57.1 ancestral haplotype characterized by HLA-B*5701, C4A6 and HLA-DR7, -DQ3 in 72% of the ABC HSR pts (OR = 822, Pc < 0.00001).
Methods: We evaluated 200 HIV-infected pts exposed to ABC for ABC HSR based on a 4-point selection criteria. From this cohort, 18 pts were ABC hypersensitive, HSR could not be excluded from 15 pts, and 167 were HSR tolerant. Pts were typed for the following MHC markers: HLA-A, -B, -C, -DR, -DQ, C4, microsatellites: D6S1014, D6S273, MIC-A, MIB, N3_3_3C2, N3_2_5, and SNPs: rs437179, rs419788, rs2072632, rs760070, rs22452572, rs7887, rs589428, rs1802189, rs1061581, rs562047, rs2227956 by standard serology and sequencing methods. Carrier frequencies were compared between groups using Fisher’s exact test and multiple comparisons were done using the Haldane modification of Woolfe’s method.
Results: Fine mapping of the hypersensitivity region on the 57.1 AH by typing microsatellite and SNP markers along this haplotype has defined the susceptibility to a region between C4A6 and D6S273 (Megakaryocyte transcription factor 1 [MEGT1]). Further refinement was then performed on a restricted pt set that included the 18 HSR pts and 12 abacavir tolerant pts recombinant for the 57.1 AH. The presence of the non-57.1AH SNP alleles (rs437179 T and rs419788 A in SKI2W) in an informative tolerant pt helps define the centromeric end of the susceptibility region. The N3_2_5 microsatellite centromeric of SnRNP is carried by the ABC HSR pts and the informative tolerant controls and marks the telomeric boundary of the susceptibility region.
Conclusions: This data confirms the 57.1 ancestral haplotype specific linkage disequilibrium and narrows the location of the putative hypersensitivity gene(s) to a 150 kb region flanked by SKI2W and SnRNP within the central MHC.
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|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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