Polymorphism haplotypes and disease

The MHC is highly polymorphic including single nucleotide polymorphisms (SNPs), deletion/insertion (indel) polymorphisms, and copy number variation, with strong patterns of coinheritance or linkage disequilibrium between given genetic variants. Such patterns of association between alleles may arise through recombination events, gene conversion, demography, genetic drift, and natural selection. Defining the common combinations of particular alleles, the haplotypic structure, helps us to understand the ancestral origin of genetic diversity. The extensive linkage disequilibrium seen at the MHC facilitated early studies to define the importance of this genomic region in susceptibility to a range of different autoimmune, infectious and other diseases through typing serological or genetic markers. It has also led to considerable challenges in subsequently fine mapping disease associations and resolving specific functional variants. Given the biological and medical interest of genetic variation in the MHC, the patterns of linkage disequilibrium, the hotspots of recombination, and the haplotypic structure of this genomic region have been the subject of intense research for several decades. The extreme levels of polymorphism found in the MHC and the extent of linkage disequilibrium has made defining the haplotypic structure particularly challenging, but a clearer picture is starting to emerge.

12.3.1 Infectious disease, selection, and maintenance of MHC polymorphism

Susceptibility to infectious disease has been postulated as a major driving force in the maintenance of polymorphism at class I and II loci in the MHC. The finding that susceptibility to malaria was associated with the possession of particular HLA alleles was consistent with this hypothesis, a notable study being that by Hill and colleagues who determined that in a large cohort of children with malaria in The Gambia in West Africa, possession of HLA-B53 was associated with protection from severe malaria (Section 13.2.6) (Hill et al. 1991). Malaria and other infectious diseases have represented major selective forces during human history, and are significant determinants of the patterns of genetic diversity we observe today (Section 13.2). Individuals who are heterozygous for HLA alleles have been proposed to be at an advantage within a population because the greater repertoire of MHC molecules would allow them to present up to twice as many peptides from pathogens as homozygous individuals, and hence mount a more effective immune response (Doherty and Zinkernagel 1975a).

The much higher than expected rate of nonsynony-mous (amino acid changing) nucleotide substitutions within coding regions for peptide binding in MHC molecules compared to other areas of the MHC is consistent with Darwinian selection operating at these gene loci (Hughes and Nei 1988, 1989). Analysis of HLA-A and -B showed significantly less homozygosity than expected given neutrality (Hedrick and Thomson 1983), with amino acid heterozygosity concentrated in peptide binding regions when diversity across different human populations was studied (Hedrick et al. 1991). Finding clear evidence of heterozygote advantage in terms of disease susceptibility has, however, been surprisingly difficult. Examples have been found for a number of viral infections. Maximal heterozygosity at HLA-A, -B, and -C loci has been associated with delayed onset of acquired immuodeficiency syndrome (AIDS) and lower mortality in HIV-1 infection (Section 14.4) (Carrington et al. 1999). Heterozygosity of class II alleles has been associated with clearance of hepatitis B (Thursz et al. 1997), while heterozygosity at all class I loci was associated with a lower proviral load of human T cell lymphotropic virus type I, consistent with a strong class I restricted cytotoxic T lymphocyte response reducing infection and disease risk (Jeffery et al. 2000). Analysis of isolated populations has also proved informative, with substantially less homozygotes than expected found on serological testing for HLA-A and HLA-B among South Amerindian tribes (Black and Hedrick 1997). Black and colleagues studied children of families in 23 tribes from the Amazon and Orinoco basins and found approximately 25% less homozygotes than from mendelian expectations.

Is heterozygote advantage (also known as overdominant selection) sufficient to account for the observed degree of variation at the MHC? The answer remains unclear but other factors such as mate selection and preferential abortion may be important, as well as host-pathogen coevolution. Here, greater evolutionary fitness is associated with individuals possessing new rare MHC alleles with the potential to present peptides from pathogens that have avoided presentation by common MHC molecules (Borghans et al. 2004). Such a situation is postulated for HIV infection where the virus adapts to common MHC alleles in a population, giving a selective advantage to those with rare alleles (Trachtenberg et al. 2003).

12.3.2 Ancestral haplotypes

Ancestral haplotypes (also known as conserved extended haplotypes) are large chromosomal segments that have been conserved en bloc, with a fixed constellation of alleles. In the case of the MHC, such haplotypes can span several megabases, for example from HLA-B to HLA-DR (Degli-Esposti et al. 1992). Ancestral haplotypes have been named with reference to the HLA-B allele, followed by a number denoting the order of discovery. The 8.1 haplotype, bearing HLA-A1-B8-Cw7-DR3, is perhaps the most intensively studied of any ancestral haplotype with many significant associations with autoimmune diseases including susceptibility to type 1 diabetes, coeliac disease, systemic lupus erythematosus, myasthenia gravis, dermatitis herpetiformis, common variable immunodeficiency, and IgA deficiency, as well as survival after HIV-1 infection

(Box 12.4) (Price et al. 1999). The extent of conservation between HLA-A in the class I region and HLA-DQ in the class II region is remarkable: recent analysis of 656 SNPs within 4.8 Mb of the MHC among 31 examples of 8.1 haplotypes showed greater than 99% conservation over a 2.9 Mb region (Aly et al. 2006).

Why should such a long region be conserved? Natural selection is perhaps the most attractive hypothesis. The high frequency of the haplotype (10% in north Europeans) and extended length are consistent with positive selection favouring the allele(s) such that the haplotype rapidly increases in frequency before it has time to become disrupted by recombination (Section 10.2.2) (Sabeti et al. 2002a). Given a recombination rate between HLA-B and HLA-DR of 1%, the 8.1 haplotype may have arisen 23-40 generations ago (Price et al. 1999). Suppression of recombination is another mechanism whereby long range conservation may have arisen. The extreme sequence diversity and other structural differences between homologous MHC chromosomes may prevent crossovers through disruption of pairing and alignment.

12.3.3 Abacavir hypersensitivity

The 57.1 ancestral haplotype, identified by the presence of the alleles HLA-B*5701, C4A6, HLA-DRB1*0701 (DR7) and HLA-DQB1*0303 (DQ3), is of particular interest given its association with hypersensitivity to the anti-retroviral drug abacavir (Mallal et al. 2002). Abacavir is a nucleoside analogue which in approximately 5% of white patients with HIV infection will produce a characteristic hypersensitivity reaction including fever, rash, and gastrointestinal symptoms. The reaction shows familial clustering and racial differences in frequency, and can be life threatening on re-exposure to the drug.

In the Western Australian HIV Cohort Study, the 57.1 haplotype showed a remarkable level of association with abacavir hypersensitivity. In a cohort of 200 individuals,

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