Disease Associations

In 1973, the first association between an HLA haplotype and a disease—ankylosing spondylitis—was identified. Since then, more than 100 other disease associations have been established, including several for ocular inflammatory diseases (Table 4-1). An HLA–disease association is established when there is a statistically increased frequency of an HLA haplotype in persons with that disease compared with the frequency in a disease-free population. The ratio of the probability of the disease occurring in individuals with the HLA haplotype to individuals without the haplotype is termed relative risk. A relative risk of 1 denotes no difference in risk, <1 indicates a reduced risk, and >1 an increased risk. Several points are important when considering HLA–disease associations:

• The HLA association identifies individuals at risk, but it is not a diagnostic marker. The associated haplotype is not necessarily present in all people with the disease, nor does its presence in a person ensure the correct diagnosis.

• The association depends on the validity of the haplotyping. Older literature often reflects associations based on HLA classifications (some provisional) that might have changed.

• The association is only as strong as the clinical diagnosis. Diseases that are difficult to diagnose based on clinical features may obscure real associations.

• The concept of linkage disequilibrium proposes that if 2 genes are physically close together on a chromosome, they are likely to be inherited together rather than undergo genetic randomization in a population. Thus, HLA genes may be coinherited with a separate gene that confers the actual risk. Sometimes 2 HLA haplotypes can occur together more frequently than predicted by their independent frequencies in the population.

For example, approximately 8% of the Caucasian population in the United States is HLA-A29 positive, but fewer than 1 in 10,000 US residents have birdshot chorioretinopathy (although nearly all patients with birdshot chorioretinopathy are HLA-A29 positive). Thus, most individuals who are HLA-A29 positive will never develop birdshot chorioretinopathy. This reinforces that other genetic and environmental factors are implicated. As an example, genes encoding aminopeptidases involved in processing of MHC class I ligands, namely endoplasmic reticulum aminopeptidase (ERAP), have been identified in genome-wide association studies of patients with birdshot chorioretinopathy.

Table 4-1 HLA Associations and Ocular Inflammatory Disease

Several mechanisms have been proposed for HLA-disease associations. The most direct theory postulates that HLA molecules act as peptide-binding molecules for etiologic antigens or infectious agents. Thus, individuals bearing a specific HLA molecule might be predisposed to processing certain antigens, such as an infectious agent that cross-reacts with a self-antigen, and other individuals, lacking that haplotype, would not be so predisposed. Specific variations or mutations in the peptide-binding region would greatly influence this mechanism; only molecular typing can detect these variations. Preliminary data in support of this theory is available for patients with type 1 diabetes mellitus.

A second theory proposes molecular mimicry between bacterial antigens and an epitope on the HLA molecule (ie, an antigenic site on the molecule itself). An appropriate antibacterial effector response might inappropriately initiate a cross-reactive effector response with an epitope of the HLA molecule.

A third theory suggests that the T-lymphocyte antigen receptor (gene) might be the true susceptibility factor. Because a specific T-lymphocyte receptor uses a specific HLA haplotype, a strong correlation would exist between an HLA and the T-lymphocyte antigen receptor repertoire.

• Kuiper J, Rothova A, de Boer J, Radstake T. The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers. Prog Retin Eye Res. 2015;44:99–110.

• Levinson RD. Immunogenetics of ocular inflammatory disease. Tissue Antigens. 2007;69(2):105–112.

Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.