Genetic polymorphisms and uveitis
Authors: Abramowicz Stéphane 
Published: January 2025

Uveitis is a multifactorial disease, originating from the interplay between our genes, the environment and stochastic factors.1 In contrast, only a handful of exceptional uveitic entities are monogenic.

To understand the immunogenetics of uveitis, one must understand the concept of multifactorial disease. These diseases are characterized by multigenic involvement, with any one variant allele being neither necessary nor sufficient for disease initiation. Rather, it is the combination of multiple variants in multiple genes, which all increase the susceptibility of an individual to develop a particular disease. The second concept is that of the environmental trigger, such as an infection or exposure to a drug, which triggers the disease in genetically susceptible individuals. Stochastic factors may also play a role in disease genesis.2

In the context of uveitis, genetic polymorphisms in genes of the class I major histocompatibility complex (MHC), such as HLA‐A, or HLA‐B, are associated with common non‐infectious uveitides (NIU) like HLA‐B27‐associated acute anterior uveitis (AAU), Behçet's disease, and Birdshot retinochoroiditis (BRC).3

Specifically, HLA‐B27 carrier frequency in the Caucasian US population is around 7%, while it is present in approximately 50% of patients who develop AAU, and 90% of patients who develop ankylosing spondylitis (AS). This represents a relative risk (RR) for carriers of HLA‐B27 of around 8 for developing AAU,4 and around 50 to 100 for developing AS.5

HLA‐B51 carrier frequency in populations along the Silk Road is around 10‐30%,6 compared to 50‐80% in Behçet's disease patients, conferring a RR of 5‐10 to develop the disease.7

The third major HLA polymorphism associated with uveitis is HLA‐A29, whose carrier frequency in the Western European population is reported to be 5‐10%,8 compared to the 97.5% in BRC patients,3,9 conferring an astronomically high RR of 50‐224 for developing BRC in carriers of HLA‐A29 versus non‐carriers.4,9 BRC is actually the immunological disease with the strongest HLA association ever described.4

Some weaker HLA associations have been reported with other NIU entities, such as HLA‐DR4/HLA‐DRB1*04 with Vogt‐Koyanagi‐Harada disease,10,11 HLA‐DRB1*04:05, HLA‐DQB1*04:01, and the DRB1*04:05‐DQB1*04:01 haplotype with sympathetic ophthalmia,12 or HLA‐DRB1*15:01 and the IL2‐RA gene polymorphism rs2104286 A>G with multiple sclerosis‐associated uveitis.13

In addition to HLA typing and polymorphisms, there has been much interest in evaluating single‐nucleotide polymorphisms of various mediators of the immune response. For example, polymorphisms in the ERAP1, ERAP2 or IL‐23R genes, have been described in association with uveitis.14,15 Many other associations have been described.

That being said, the reason why these genetic associations predispose individuals to immunological disease remains a mystery. Some of the hypotheses put forward over the years include interaction of the HLA molecules with the gut microbiome resulting in increased gut permeability and leakage of bacterial products in the circulation, while others think molecular mimicry acting as a trigger for activation of autoreactive lymphocytes specific for the neuroretina might play a role.16–18

In summary, genetic polymorphisms play a major role in the immunogenetics of some prevalent NIU entities. These may help shape our understanding of pathophysiological mechanisms in the future.

References:

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