rs116488202 (HLA-B27): Uveitis and Spondylitis Risk

Key takeaways

• rs116488202 is the standard genetic marker (tag SNP) for HLA-B27, a cell-surface immune protein present in more than 50% of people with primary acute anterior uveitis.
• HLA-B27 carriers face roughly a 1% lifetime risk of uveitis, about five times higher than the general Caucasian population rate of 0.2%.
• Ankylosing spondylitis (a painful spinal inflammatory arthritis) occurs in 30-40% of individuals who have both HLA-B27 positivity and uveitis, highlighting substantial genetic overlap between the two conditions.
• The alternate allele of rs116488202 is linked to reduced expression of MICA-AS1 (a long non-coding RNA near the immune gene MICA) across at least eight tissue types, including skin, arteries, and nerve.
• Only a minority of HLA-B27 carriers develop either uveitis or ankylosing spondylitis, indicating that additional genetic and environmental factors beyond this variant contribute to risk.

What the research says rs116488202 tags the HLA-B27 allele within the major histocompatibility complex (MHC, the chromosome 6 region encoding most immune recognition proteins) and shows genome-wide significant association (P < 5 x 10^-8) with acute anterior uveitis (AAU, inflammation of the front of the eye) when comparing 1,711 AAU patients against 10,000 healthy controls on the Illumina Immunochip microarray platform. More than 50% of individuals with primary AAU test positive for HLA-B27, and HLA-B27 carriers have a cumulative incidence of AAU of approximately 1%, compared to 0.2% in the general Caucasian population. HLA-B27 (tagged by this SNP) is also the primary genetic driver of ankylosing spondylitis (AS), carried by more than 80% of European-ancestry AS patients in a study of 10,619 AS cases and 15,145 controls, with AS heritability estimated above 90% and a sibling recurrence risk ratio greater than 52.

Reported associations

• Acute anterior uveitis (AAU): genome-wide significant association (P < 5 x 10^-8) over the HLA-B locus, identified in a dataset of 1,711 AAU cases (1,199 with co-morbid AS, 238 with AAU alone) vs. 9,564 quality-controlled controls; more than 50% of primary AAU cases carry HLA-B27.
• Ankylosing spondylitis (AS): HLA-B27 (tagged by rs116488202) is carried by more than 80% of European-ancestry AS patients; AS affects approximately 0.55% of European-ancestry populations and 0.23% of Chinese populations, and is 2-3 times more prevalent in men than women.
• AAU and AS co-morbidity: uveitis occurs in 30-40% of individuals with AS, and a heterogeneity analysis found that several confirmed AS-associated loci show significantly different effect sizes in AS patients with co-morbid AAU versus those without, indicating partly distinct genetic architecture.

Evidence quality The association of rs116488202 with AAU was demonstrated in one of the largest AAU genetic studies assembled to date, achieving genome-wide significance (P < 5 x 10^-8) on the Illumina Immunochip platform with 1,711 AAU cases and 9,564 controls after quality control. For AS, a separate Immunochip study of 10,619 cases and 15,145 controls across European, East Asian, and Latin American ancestry groups reported a genomic inflation factor of 1.047, indicating minimal residual population stratification. HLA-B27 association with both AAU and AS is among the most replicated findings in human genetics, and no conflicting findings regarding the direction of rs116488202 association are reported across the studies reviewed here. The primary caveat is that only 1-5% of HLA-B27 carriers develop AS and approximately 1% develop AAU, meaning additional genetic and likely environmental factors are required for disease onset and this variant alone does not determine outcome.

Tissue-specific expression effects

• MICA-AS1: the alternate allele of rs116488202 is linked to substantially reduced expression of MICA-AS1 (a long non-coding RNA located near the MICA gene, which encodes a stress-signaling ligand recognized by natural killer immune cells) across at least eight tissues, including tibial artery, tibial nerve, sun-exposed lower-leg skin, non-sun-exposed suprapubic skin, subcutaneous adipose, visceral omental adipose, esophageal muscularis, and esophageal gastroesophageal junction, with highly significant associations (p-values as low as 8.2 x 10^-30). These are tissue-level expression effects reflecting a potential mechanism; their functional and clinical significance is not yet established. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.