Lack of association of C3 gene with uveitis: additional insights into the genetic profile of uveitis regarding complement pathway genes

Abstract

Uveitis is a devastating ocular disease that causes blindness. Our previous studies have achieved great advancements in depicting the genetic profiles of uveitis regarding complement pathway genes. This study aimed to provide additional insights into this interest by testing the "central" factor of the complement system, C3 gene variants, in two uveitis entities. Eight haplotype-tagging SNPs of C3 gene were genotyped in 141 anterior uveitis (AU), 158 non-infectious intermediate and posterior uveitis (NIPU) and 293 controls. The results showed that none of the tagging SNPs had a significant association with uveitis (P > 0.05), either in the global uveitis or subtypes. Although rs428453 showed a nominal association with NIPU subtype in the recessive model (P = 0.042), the P value could not withstand the Bonferroni correction (P corr > 0.05). Stratification analyses according to HLA-B27 status and correlation analysis still did not find any significant interactions or genetic markers regarding AU. Logistic regression analysis also revealed no gender-related epistatic effects of C3 on uveitis. Two haplotype blocks were defined across the C3 locus but neither of them was significantly associated with uveitis or subtypes. This study shows no significant association of the C3 gene with uveitis, suggesting C3 confers either no or limited risk for uveitis susceptibility.Uveitis is a group of heterogeneous ocular inflammatory diseases with complex phenotypes, which is considered as a substantial visual impairment as well as an important socio-economic problem, being the fourth cause of blindness worldwide 1, 2 . Uveitis can be frequently classified into anterior uveitis (AU), intermediate uveitis (IU), posterior uveitis (PU), and panuveitis according to the anatomical location of the inflammation 3 . AU, which refers to inflammation of the iris and ciliary body, is the most common form found in clinics. Although less common than AU, non-infectious intermediate and posterior uveitis (NIPU) typically is either idiopathic and comprises many well-defined uveitic ocular conditions or associated with systemic underlying autoimmune disorders, including Vogt-Koyanagi-Harada disease (VKH), Behçet's disease (BD), and sarcoidosis 3,4 .Although the exact pathogenesis of uveitis remains unclear, it is generally accepted as an inflammatory condition and mainly mediated by various endogenous immunological mechanisms 5 . Moreover, genetic factors in the initiation and development of uveitis have been recognized for a few decades [6][7][8][9][10][11] .The complement system is a key component of innate immunity and plays an important role in modulating various immune and inflammatory responses. The activation of the complement system occurs along three routes -the classical, alternative, and lectin pathways 12 . Notably, in recent years, accumulating studies have provided increasing evidence that complement is involved in the pathogenesis of uveitis. These studies revealed that activation of the complement system is critical for the develo...

Genetic profiling of ocular inflammation: further evidence for a gender-specific association of C5 with uveitis

“…Of them, variants in the CFH, CFB and CFI involved in the alternative pathway, were identified as genetic risk markers for various uveitis subtypes [16][17][18][19][20]. A recent report from our laboratory also demonstrated that the classical pathway gene, C1INH, as well as the central component of the cascade, C3 gene, may confer either no or limited risk for uveitis susceptibility [21,22]. Overall, our findings together suggest that the alternative pathway as well as the "upstream" cascade of complement system confers major genetic impact on uveitis susceptibility.…”

“…The genotypes were read by the system software (Prism 7000 SDS software version 1.1; ABI). More details were described in our previous studies [20,22].…”

“…Our research team have made great efforts in depicting the genetic profile of uveitis and intraocular inflammation regarding complement pathway genes, several genes have been extensively investigated and identified to be associated with many forms of uveitis, these genes included complement factor H (CFH), complement factor B (CFB), complement factor I (CFI), and CD59 [15][16][17][18][19][20]. Meanwhile, we have largely ruled out the involvement of some complement factors in the disease genetics, such as component 1 inhibitor (C1INH), and complement component 3 (C3) [21,22]. Notably, some genetic associations between AU and complement genes were also found in NIPU patients in our study cohort, suggesting that these two uveitis entities shared general genetic background although presenting different clinical phenotypes.…”

Intermediate Uveitis

“…Such associations were not found for the interleukin-23 receptor single-nucleotide polymorphisms (SNPs) reported in other autoimmune diseases [43]. Complement C3 SNPs also lacked an association with non-infectious intermediate and posterior uveitis [44], although polymorphisms in the Complement Factor H gene implicated in age-related macular degeneration were statistically increased compared to controls in patients with intermediate uveitis [45]. Interplay between cytokine polymorphisms was proposed to alter prognosis in intermediate uveitis [46].…”

CFH I62V as a Putative Genetic Marker for Posner-Schlossman Syndrome

“…The complement system, a key innate immune defense system, plays an important role in modulating various immune and inflammatory responses. In our previous studies, we intensively studied the genetic profiles of complement pathway genes in uveitis, including complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), complement component 3 (C3), complement component 5 (C5), and complement component 1 inhibitor gene (SERPING1) (9)(10)(11)(12)(13)(14)(15)(16)(17). Moreover, recent studies have implicated complement cascades in glaucomatous neurodegeneration.…”