Genetic Dissection of Acute Anterior Uveitis Reveals Similarities and Differences in Associations observed with Ankylosing Spondylitis

Acute anterior uveitis (AAU) has a cumulative incidence rate in the Caucasian general population of 0.2%, but in those who are HLA-B27 positive (8–10% of the Caucasian population) the cumulative incidence rate is 1%[1]. Recurrent AAU may lead to glaucoma, cataract development and significant visual loss. Uveitis is a major cause of eye disease, affecting an estimated 2 million Americans, and accounts for up to 10% of blindness[2, 3]. Evidence from both humans and animal models suggests a large genetic component to uveitis with strong familiality demonstrated[4]. The first-degree recurrence risk of AAU is 6% compared to a population prevalence of only 0.038–0.38%[5]. AAU occurs in 30–40% of individuals with ankylosing spondylitis (AS) suggesting a shared etiology[6]. It is strongly associated with HLA-B27 both in those with AS, and those without, with more than 50% of those with primary AAU being HLA-B27 positive[7]. There is evidence that genes other than HLA-B influence the risk of developing AAU. The prevalence of AAU in the HLA-B27 positive first-degree relatives of probands with AAU (13%) is much higher than in the normal HLA-B27 positive (Dutch) population (1%), indicating that other genetic factors besides HLA-B27 are involved[5]. In the same study, 11% of HLA-B27 positive first-degree relatives >45 years of age had AS compared with an expected frequency of AS in HLA-B27 carriers of ~1%, highlighting the strong co-familiality of AS and AAU. Other genetic associations described for AAU include HLA-A*02[8], HLA-DRB1*08:03[9], HLA-B*58[10], MICA[11], LMP2[12], CYP27B1[13], IL10[14], the complement components CFB, CFH and C2[15, 16], TNF[17, 18], the Killer Immunoglobulin Receptor (KIR) region[19], and suggestive linkage has been reported to the chromosome 9p region[20]. No findings have achieved genomewide significance (P < 5×10−8), and few associations have been replicated[6]. Few of these studies were adequetely powered to identify genes involved in AAU reliably so we sought to investigate its association in the largest data set assembled for this purpose to date.