Which genes are associated with anterior uveitis in a patient who is HLA‑B27 negative?

Genetic Associations with HLA-B27 Negative Anterior Uveitis

In HLA-B27 negative anterior uveitis, the most important genetic associations identified through genome-wide analysis include ERAP1, INAVA, TNRC18, IL23R, NLRP3, NOS2, and HDAC2-AS2, with these loci showing genome-wide significant associations independent of HLA-B27 status. 1

Primary Non-HLA Genetic Loci

The largest and most recent genome-wide association study (GWAS) meta-analysis of 12,205 anterior uveitis cases identified six genome-wide significant loci, three of which represent novel discoveries 1:

Novel Loci (First Identified 2025)

• INAVA (innate immunity activator): Genome-wide significant association (p<5×10⁻⁸), also associated with inflammatory bowel disease and other immune-related phenotypes 1
• NLRP3 (nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3): Genome-wide significant association, involved in inflammasome activation 1
• NOS2 (nitric oxide synthase 2): Genome-wide significant association with anterior uveitis 1

Previously Identified Loci Confirmed

• ERAP1 (endoplasmic reticulum aminopeptidase 1): Genome-wide significant association, also strongly associated with ankylosing spondylitis and inflammatory bowel disease 1
• TNRC18 (trinucleotide repeat containing 18): Genome-wide significant association, linked to other immunity-related phenotypes 1
• IL23R: Replicated association with acute anterior uveitis 1
• HDAC2-AS2: Replicated association with acute anterior uveitis 1

Clinical Context and Interpretation

Genetic Architecture Beyond HLA-B27

While HLA-B27 is present in approximately 50% of anterior uveitis patients, the remaining 50% are HLA-B27 negative 2. Historical family studies demonstrated that not all relatives with acute anterior uveitis share the HLA-B27 positive haplotype—in one analysis, 1 of 7 affected relatives was HLA-B27 negative, and another carried a different HLA-B27 positive haplotype than the proband 2. This confirms that genetic susceptibility extends beyond HLA-B27.

Shared Genetic Pathways with Other Immune Disorders

The genetic correlation between anterior uveitis and inflammatory bowel disease is moderate (rg=0.39, p=8×10⁻⁵), indicating shared pathogenic mechanisms 1. Lead SNPs at ERAP1, INAVA, and TNRC18 loci are associated with both anterior uveitis and other immune-mediated conditions including ankylosing spondylitis and inflammatory bowel disease 1.

Historical Genetic Investigations

Earlier HLA Studies (Limited Current Relevance)

Older studies from the 1980s investigated whether other HLA antigens beyond B27 contributed to uveitis risk:

• HLA-A2: In HLA-B27 positive AS patients, those with HLA-A2 had 35% prevalence of uveitis versus 14% without A2 (p<0.025), though this finding is specific to the B27-positive population 3
• HLA-Cw1, Cw2, DR4, DRw12, DQw3: Initial associations disappeared when compared to HLA-B27 positive controls, indicating these were due to linkage disequilibrium rather than independent effects 2

These older HLA associations have limited clinical utility in HLA-B27 negative patients and have been superseded by modern GWAS findings. 2

Clinical Implications

Diagnostic Approach

For HLA-B27 negative anterior uveitis patients, genetic testing beyond HLA-B27 is not currently recommended for routine clinical practice, as the identified loci do not yet have validated clinical utility for diagnosis or risk stratification 4. The 2018 consensus guidelines explicitly state that "advances in genetics have not found any more specific diagnostic markers than the HLA types originally reported" and "there is no evidence, at present, that genotyping adds specificity to the established clinical risk factors" 4.

Screening for Associated Conditions

Given the genetic overlap with inflammatory bowel disease and spondyloarthritis, HLA-B27 negative anterior uveitis patients should be evaluated for 1:

• Inflammatory bowel disease symptoms (diarrhea, abdominal pain, weight loss)
• Inflammatory back pain characteristics (morning stiffness >30 minutes, improvement with exercise, nocturnal pain) 5
• Peripheral arthritis or enthesitis

Important Caveats

• Approximately 10% of ankylosing spondylitis cases are HLA-B27 negative, so absence of B27 does not exclude spondyloarthritis 5
• The newly identified genetic loci (INAVA, NLRP3, NOS2) require validation in independent cohorts before clinical application 1
• Genetic testing for these novel loci is not commercially available or clinically indicated at present 4