Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective

Abstract

Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (P corr = 0.032, OR = 0.65 and P corr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (P corr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.

Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina

“…Single-nucleotide polymorphisms in complement genes are associated with a number of retinal diseases, including glaucoma (Scheetz et al, 2013), age-related macular degeneration (AMD) (Weber et al, 2014), and diabetic retinopathy (Yang et al, 2016; Wang et al, 2013). The immune-privileged retina is among others under regular immune surveillance by proteins of the complement system.…”

The eye as a complement dysregulation hotspot

“…One study found the intronic SNP rs2269067 in the C5 gene to be associated with proliferative diabetic retinopathy in the Chinese Han population, and this SNP was shown to be associated with increased C5 mRNA expression [ 20 ]: the study also noted an increase in the production if IL-6 associated with the rs2269067 SNP. Another study found a weak association between the coding SNP rs17611 (which results in the V802I polymorphism in the C5 protein previously associated with rheumatoid arthritis [ 23 ]) and diabetic retinopathy in type 2 diabetes [ 24 ]. Given the data linking diabetic retinopathy to complement over-activation, it has been suggested that anti-complement therapeutics have potential for treating diabetic retinopathy [ 22 ].…”

Diabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy

“…2016a; Yang et al. 2016a). Complement factors B (CFB ) is a competitor of CFH and both regulate the activation of the complement alternative pathway (Wang et al.…”

“…Yang et al. (2016a) analysed six polymorphisms (rs12237774, rs2269066, rs17611, rs1548782, rs10985126 and rs1017119) in the gene encoding C5 in their Chinese cohort. They found that two of the SNPs were associated with DR (rs17611 and rs1548782).…”