Genetic Variants of Interleukin 17A Are Functionally Associated with Increased Risk of Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Interleukin 17 (IL-17) is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. In the current study, we examined two single nucleotide polymorphisms (SNPs), rs2275913G/A and rs3748067C/T, in the IL-17A gene between AMD patients and healthy controls. Results showed that rs2275913AA genotype and rs3748067TT genotype were associated with increased susceptibility to AMD (hazard ratio [HR], 1.75; 95 % confidence interval [CI], 1.07 to 3.02; P=0.023, and HR, 2.12; 95 % CI, 1.26 to 4.01; P=0.004; data were adjusted for age and sex). Next, we investigated the functional relevance of the two SNPs. In vitro stimulated peripheral blood mononuclear cells (PBMCs) from subjects possessing the rs2275913AA genotype produced significantly more IL-17 than those with the GG genotype. However, PBMCs with rs3748067TT genotype revealed significantly higher IL-17 production than those with rs3748067CC genotype only in AMD patients but not in controls. These data indicate IL-17A polymorphisms are associated with increased risk of AMD probably by affecting gene expression.

Systemic frequencies of T helper 1 and T helper 17 cells in patients with age-related macular degeneration: A case-control study

“…reported that complement component C5a is increased in the circulation of AMD patients and that it promotes expression of the Th17 cytokines IL-17 and IL-22 by human CD4 + T-cells 41 . Also, an association between two single nucleotide polymorphisms in the IL-17 gene, rs2275913G/A and rs3748067C/T and AMD was reported 42 . IL-17 and TNF-α have been observed at higher concentrations in AMD patients and may be linked to a more favorable response to anti-VEGF therapy 43 .…”

Inflammatory Mechanisms of Age-related Macular Degeneration

“…49 Two SNPs within the IL-17A gene were recently reported to be associated with AMD as well as higher levels of IL-17A secretion from PBMC stimulated ex vivo . 62 Elevated IL-17A and IL-17RC levels were also detected in AMD lesions compared with normal macular tissues. 51 In vitro, IL-22 induced apoptosis of primary human RPE cells, 63 and IL-17A was shown to enhance production of inflammatory cytokines, including IL-6, IL-8 and CCL2, from ARPE-19 cells 64 as well as induce angiogenesis in human choroidal endothelial cells.…”

Association of Choroidal Interleukin-17-Producing T Lymphocytes and Macrophages with Geographic Atrophy

“…An increase of IL-17 immunopositivity has been reported in GA eyes compared to control subjects, but IL-17-producing cells could not be identified [27]. Furthermore, genetic variants of IL-17 have been shown to be associated with AMD [28], while the reported association of hypomethylation of the IL-17 receptor [27] was not reproducible in another study [29]. …”