Association between the SERPING1 gene and age-related macular degeneration: a two-stage case–control study

Abstract

Summary Background Age-related macular degeneration is the most prevalent form of visual impairment and blindness in developed countries. Genetic studies have made advancements in establishing the molecular cause of this disease, identifying mutations in the complement factor H (CFH) gene and a locus on chromosome 10 encompassing the HTRA1/LOC387715/ARMS2 genes. Variants in complement 3 (C3) and an HLA locus containing both factor B and C2 genes have also been implicated. We aimed to identify further genetic risk factors for this disease. Methods We used a case–control study design in a UK sample of patients with age-related macular degeneration (n=479) and controls (n=479) and undertook a low-density screen of 32 genes using 93 single nucleotide polymorphisms (SNPs). Genes were selected as candidates on the basis of potential functional relevance to age-related macular degeneration. Significant initial findings were confirmed by replication in an independent US cohort of 248 unrelated patients with disease and 252 controls, and by high-density genotyping around association signals. Findings The SNP variant rs2511989, located within intron six of the SERPING1 gene, showed highly significant genotypic association with age-related macular degeneration (uncorrected p=4·0×10−5, corrected p=0·00372). We detected no evidence for association between disease and the other 31 candidate genes. The odds ratio for age-related macular degeneration in rs2511989 G/A heterozygotes compared with wild type G/G homozygotes was 0·63 (95% CI 0·47–0·84). A similar comparison of the A/A homozygotes with the wild type yielded an odds ratio of 0·44 (0·31–0·64). We replicated the observed genotypic association in a US cohort (p=0·008). Furthermore, a secondary high-density genotyping study across the SERPING1 gene region identified five additional SNP variants similarly associated with age-related macular degeneration (rs2244169, rs2511990, rs2509897, rs1005510, and rs2511988). Interpretation Genetic variation in SERPING1 significantly alters susceptibility to age-related macular degeneration. SERPING1 encodes the C1 inhibitor, which has a crucial role in inhibition of complement component 1 (C1) and might implicate the classic pathway of complement activation in this disease. Funding Macula Vision Research Foundation, the Macular Disease Society, the Wellcome Trust, Brian Mercer Trust, the American Health Assistance Foundation, National Institutes of Health, the Howard Hughes Medical Institute.

Complement in age-related macular degeneration: a focus on function

“…77 Subsequent studies using seven independent cohorts of AMD patients and controls failed to replicate the association with the gene variants. 78 However, a further independent study of neovascular AMD and disease-free controls 79 has recently replicated the original Ennis et al 76 findings, noting that the previous replication groups were of mixed phenotype. The SERPING1 association remains controversial, but if it becomes established, this is the first indication that the classical complement pathway may be involved in AMD pathogenesis.…”

“…A candidate gene study of complement genes by Ennis et al 76 showed an association between (mainly neovascular) AMD with SNPs in the promoter and introns of serpin peptidase inhibitor, clade G, member 1 (SERPING1), in both a UK and a USA cohort of patients. The authors showed that the gene, which is an inhibitor of complement component 1, is expressed in the retina.…”

Plasma proteomic signature of age in healthy humans

“…SERPINF2 modulates insulin sensitivity and is associated with cardiovascular diseases and diabetes (Aso et al., 2000; Uitte de Willige et al., 2011). SERPING1 modulates the complement cascade and is important in many inflammatory diseases, including macular degeneration (Ennis et al., 2008). SERPINA3 has been identified as a specific biomarker of delirium and Alzheimer's disease (Padmanabhan, Levy, Dickson, & Potter, 2006; Poljak et al., 2014).…”

Sublytic Membrane-Attack-Complex (MAC) Activation Alters Regulated Rather than Constitutive Vascular Endothelial Growth Factor (VEGF) Secretion in Retinal Pigment Epithelium Monolayers

“…Whereas mechanistic studies have shown that inflammation (1) and smoking (2) are fundamental components of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. Genetic variations with a number of complement components, including those of required activators (complement factor B, CFB) (3), inhibitors (complement factor H, CFH (4 -6); complement 1 inhibitor, C1INH, although the evidence is conflicting (7,8)) and essential components in the complement cascade (complement factor 2 and 3, C2 (3) and C3 (9)) have been found to be associated with all forms of AMD. In particular, one of the most detrimental mutations occurs in CFH (fH risk haplotype).…”