6.0 4.0 x disease incidence 0.33

1.5 1.25 x disease incidence 0.16

9.0 1.8 x disease incidence 0.80

158.4 10.4 x disease incidence 0.93

possibly stochastic events are required to elicit or trigger disease pathogenesis in predisposed individuals. The role of environmental 'triggers', such as bacterial or viral infections (or stochastic events), is evident from the observed concordance rates among monozygotic (MZ) twins. For IDDM, for example, the concordance rates for MZ twins are about 40-70%, depending on the HLA genotype.

Multiple genes

For most HLA-associated diseases, multiple genes, in addition to those in the HLA region, are involved in disease susceptibility. The polygenic nature of these disease associations can be inferred from comparing the concordance rates of HLA-identical siblings to those of MZ twins. For IDDM, for example, the concordance rates for HLA-identical sibs are 10-20% while those for MZ twins are 40-70%, implying that genes outside the HLA region are also involved. For IDDM, it has been estimated that about 45-50% of the total genetic risk can be attributed to the HLA region, based on the analysis of affected sib pairs. In addition, genome-wide scans in multiplex families have identified non-HLA genetic regions that may confer susceptibility to IDDM.

Combinations of MHC genes

In many cases, multiple genes within the HLA region appear to be involved in disease pathogenesis. For the DR4-associated susceptibility to IDDM, specific combinations of alleles at DRB1, DQA1 and DQB1 are required to confer high risk. Moreover, for IDDM, there is a hierarchy of risk ranging from highly susceptible to neutral to protective for different alleles, haplotypes and genotypes. In Caucasians, the DRB1"+1501-DQB1*0602 haplotype is strongly protective for IDDM. Among susceptible genotypes, the heterozygote DR3/DR4, DQB 1*0302 has the greatest risk for IDDM, significantly greater than the DR3/3 and DR4/4 homozygotes. One possible explanation for the dramatic DR3/4 effect on IDDM risk is the formation of iraws-complementing DQ molecules encoded by the DQA1 locus of the DR3 haplotype (*0501) and the DQB1 locus of the DR4

haplotype (*0302) and those encoded by the DQA1 locus of the DR4 haplotype (*0301) and the DQBI locus of the DR3 haplotype (*0201). For some diseases, alleles at the DPB1 locus, as well as those in the DR-DQ region appear to be involved in susceptibility. For pauciarticular juvenile rheumatoid arthritis, DPB1*0201 as well as DR8 (DRB1*0801) are strongly associated with disease and may be independent risk factors.

Interaction of host HLA genotype with pathogen genotype

For some HLA-associated diseases that are caused by an infectious pathogen, the HLA association may depend on the genotype of the pathogen. Invasive cervical carcinoma and severe cervical dysplasia result from infection with high-risk human papillomavirus (HPV) types such as HPV-16 or HPV-18. Only a small proportion of infected individuals, however, progress to cervical disease. Certain HLA types (HLA-B*07, DRBl*1501-DQB-0602, DPB1* 0401) are associated with cervical dysplasia and invasive cancer, but only with HPV-16-mediated disease.

The role of individual amino acid residues

The ability to identify specific alleles associated with a given disease has allowed the comparisons of associated sequences with other closely related alleles and made possible the identification of specific polymorphic amino acid residues that may be involved with the disease pathogenesis. Disease-associated alleles often differ from nonassociated alleles at single amino acid residues or at a single polymorphic-motif, implicating these positions as critical in some aspect of immune function, such as peptide binding and presentation. For example, the PV-associated DQBI *0503 allele differs from *0501 and "0502 only at position 57; DQBI "'0503 encodes Asp whereas "'0501 encodes Val and *0502 encodes Ser at this position. The substitution of a negatively charged residue for a neutral residue at position 57 is thought to affect the formation of a salt bridge between the a and |3 chain. In IDDM, there is a general correlation of DQB1 alleles with Asp at position 576 and low risk for IDDM; there are, however, several exceptions to this pattern. In general, the risk associated with an allele cannot be predicted by a single amino acid position but only by combinations of motifs assembled as alleles, haplotypes, and genotypes.

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