Mhc Disease Associations

Henry Erlich and Raymond Apple, Department of Human Genetics, Roche Molecular Systems, California, USA

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

The association of a disease with a genetic marker means that the frequency of a given allele at a specific locus is either increased (positive association) or decreased (negative association) among patients relative to controls. In case-control studies, a positive association indicates that the gene in question confers an increased susceptibility to the disease or is in linkage disequilibrium with a nearby allele that does. Similarly, a negatively associated gene is thought to confer protection or to be in linkage disequilibrium with another gene that is causally involved in the disease process. The relative strength of observed disease associations can be estimated by a variety of statistical measures (see below). In humans, a large number of different diseases are associated with specific alleles of loci in the HLA region (Table 1).

The human major histocompatibility complex (MHC), known as the HLA region, is located on the short arm of chromosome 6 (Figure 1) and encodes two distinct classes of highly polymorphic cell surface molecules (termed class I and class II antigens) that present peptide antigens to T lymphocytes, initiating both cellular and humoral immune responses. Over the past 30 years, a variety of diseases have been associated with alleles at the HLA loci, defined initially by serologic typing as HLA antigens. The frequency of a specific HLA antigen (e.g. HI.A-B27) can be greatly increased among patients with a specific disease (e.g. ankylosing spondylitis), an observation with important implications for differential diagnosis, identification of disease susceptibility and prognosis. The observed HLA disease associations can reflect, in principle, either some aspect of the HLA class I or class II molecules' function in the immune system or simply that the HLA loci are closely linked to and in linkage disequilibrium with other disease-conferring loci. Different HLA-associa-ted diseases can be explained by either one or the other of these basic models (see below).

Most of the diseases that show significant HLA associations are autoimmune or inflammatory disorders; in some cases, the observed HLA association was critical in suggesting the autoimmune nature of the disease, as in the distinction between type I diabetes (insulin-dependent diabetes mellitus or IDDM). a disease involving the autoimmune attack of the pancreatic islet ¡3 cells, and type II diabetes (non-insulin-dependent diabetes mellitus or NIDDM), a metabolic disease. Some autoimmune diseases, such as Reiter's syndrome are elicited in individuals with a predisposing HI.A type as a consequence of bacterial infection. Several cancers and several infectious

Table 1 A selected list of HLA class ll-associated diseases

HLA antigen

Allele or haplotype

Putative autoantigen

Autoimmune IDDM

(Type I diabetes)

Multiple sclerosis Pemphigus vulgaris

Celiac disease

Rheumatoid arthritis (RA)

Pauciarticular juvenile RA

Myasthenia gravis Stiffman's syndrome Unknown etiology Narcolepsy

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