This remains controversial. The haplotype has been associated with longevity, with differences in cellular activation and the balance of inflammatory cytokines. Low levels of IL-1 and IFNy, higher levels

of TNF, changes in the autoantibody response, and relative proportions of CD4 and CD8 T cells have all been reported.

the 57.1 haplotype was found among 13 (72%) of hypersensitive patients and none of the tolerant patients (P <0-0001) (Mallal et al. 2002). Subsequent prospective application as a genetic screening test among HIV patients prior to prescription of the drug in this population showed it performed well with a fall in incidence of drug reaction based on HLA-B*5701 testing (Rauch et al. 2006). The clinical utility of testing for HLA-B*5701 before starting treatment with abacavir has been highlighted by a recent large prospective randomised study (Box 12.5) (Mallal et al. 2008). The molecular basis for this association remain unclear but an essential role for HLA-B*5701 and the endogenous pathway for antigen presentation have been defined. The effect is specific to HLA-B*5701 and not closely related allelotypes and involves either the drug itself interacting with the antigen binding groove or causing a modification of it to allow self antigens to bind (Chessman et al. 2008).

12.3.4 Extreme polymorphism at HLA-DRB1

There are estimated to be 450 different DRB1 alleles in human populations with 13 allelic lineages, a remarkable level of diversity for one genomic locus. Like other MHC class II genes, most variation is found within the antigen recognition sites encoded by the second exon of the gene. This sequence, and diversity of it, is critical to the ability of class II molecules to present diverse antigens to T cell receptors. Balancing selection has been proposed as the driving force enhancing sequence diversity within exon 2, with a significantly higher rate of nonsynonymous versus synonymous nucleotide substitutions observed in these sequences (Hughes and Nei 1989). It remains controversial whether the different allelic lineages of HLA-DRB1 involve ancient alleles, predating hominids, or are more recent with generation through mechanisms such as gene conversion-like events.

The work of Bergstrom and colleagues proved highly informative based on analysis of the intronic sequence flanking exon 2 between alleles (Bergstrom et al. 1998; Takahata and Satta 1998). They found a small number of characteristic sequence motifs in these regions showing strong linkage disequilibrium, in a pattern consistent with allelic lineages based on serological testing. The diversity suggested evolutionary isolation over a considerable length of time with no evidence for the

Box 12.5 Pharmacogenomics and abacavir hypersensitivity

Pharmacogenomics promises to be one of the first areas of general medical care impacted by the recent rapid advances in our understanding of human genetics and its role in disease. The ability to tailor drug therapies to the individual patient so as to maximise clinical benefit while minimizing risk of adverse effects promises a radical advance in how medicine is practiced. A number of examples have already been described in this book including modulation of drug metabolism and dosage as seen with copy number variation of the cytochrome p450 genes such as CYP2D6 (Section 4.4.2); work relating to warfarin dose is described in chapter 15 (Section 15.5). In terms of risk of adverse effects, abacavir hypersensi-tivity provides one of the clearest examples to date. This was highlighted by PREDICT-1 (Prospective Randomized Evaluation of DNA Screening in a Clinical Trial), a prospective, randomized, multicenter, double-blind study of 1956 adult patients from 19 countries infected with HIV-1 (Mallal et al. 2008). The study compared the effect of screening for HLA-B*5701 before antiretroviral therapy involving abacavir with a standard of care approach without screening. Overall the prevalence in the study population of HLA-B*5701 was 5.6%. Remarkably, prospective screening completely eliminated immunologically confirmed abacavir hyper-sensitivity (0% vs 2.7%). The positive predictive value of testing for HLA-B*5701 was 58% (in other words the allele was necessary but not sufficient for hypersensitivity) while most importantly the negative predictive value of the test was 100%. This large prospective trial clearly showed the clinical utility of HLA-B*5701 as a pharmacogenomic biomarker in identifying at risk individuals and testing for HLA-B*5701 before commencing abacavir therapy is now recommended in guidelines from US Department of Health and Human Services.

Intron 1 Exon 2 Intron 2

P sheet a helix

Intron 1 Exon 2 Intron 2

P sheet a helix

0 0

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