Correspondence

The SERPING1 gene and age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world. It is a complex multifactorial disease, and despite new advances in treatment, many patients still succumb to visual impairment. The complement pathway has been implicated in the pathogenesis of many diseases, and recently variants in several genes encoding complement pathway proteins have been associated with AMD. Complement proteins have been found in histological specimens of eyes with AMD. Altered levels of both intrinsic complement proteins and activated products have been found in the circulation of patients with AMD. Complement activation may be triggered by oxidative stress, resulting from retinal exposure to incoming light; indeed an inter-play between these two pathological processes seems to exist. Finally, complement inhibitors are currently being evaluated in clinical trials. This article reviews the role of the complement system in AMD, and the potential of complement inhibition in preventing the devastating blindness resulting from this disease.

Systemic complement activation is associated with age-related macular degeneration (AMD) and has mainly been attributed to a risk allele in the complement factor H (CFH) gene. Whether other important AMD genes also influence complement activation is unclear. In the present case-control study, complement activity and concentrations of complement components and their activation products are measured in AMD patients and in unaffected controls and correlated with genetic variants in the CFH, ARMS2, C3, CFI, and CFB genes.

Case-control study.

A cohort of 197 confirmed AMD patients and 150 unaffected age-matched controls were recruited prospectively for the study.

Hemolytic complement assays (AP50, CP50, and LP50), complement components (C3, CFB, CFI, and CFH), and the activation products (C3d, C5a, and SC5b-9) were analyzed in serum or plasma. The DNA samples were genotyped for 5 single nucleotide polymorphisms (SNPs) previously associated with AMD in the CFH, ARMS2, C3, CFB, and CFI genes.

Complement concentrations and their associations with SNPs in the CFH, ARMS2, C3, CFB, and CFI genes.

The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation. While the CFH risk genotype was significantly associated with the elevated C3d/C3 ratios obtained, in the absence of CFH risk alleles the ARMS2 risk genotype also showed significantly increased levels of complement activation (P = 0.013). Furthermore, the carriers of the CFB protective allele had lower CFB concentrations.

The current study found evidence showing that in AMD risk alleles in CFH and ARMS2 are independently associated with complement activation. Especially the C3d/C3 ratio seems to be a strong marker for AMD. The findings suggest that CFH and ARMS2 share a common pathway in the pathogenesis of AMD.

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

This study assessed variation in plasma levels of the complement regulatorC1 inhibitor (C1inh) in patients with age related macular degeneration (AMD) and controls. Plasma from391 AMD cases and 370 controls was assayed by rate nephelometry to determine C1inh protein levels. Protein levels were analysed for relationships with age, gender, smoking, AMD disease status and genetic variation in the SERPING1 gene, which encodes C1inh, using a multivariate analysis. t-Tests show a significant difference in C1inh levels in AMD cases compared with controls (p = 2.340E-6), smokers compared to non-smokers (p = 1.022E-4) and females compared to males (p = 1.661E-7). Multivariate analysis shows that after accounting for gender and smoking AMD status remained significant. Age was included in the model but was not significant. Including genetic variation in the model shows that one significant SNP (rs2649663) 5′ of the SERPING1 gene is associated with C1inh levels though this SNP is not associated with AMD. This suggests that genetic variation in the promoter region of the SERPING1 gene may influence expression of the gene.

During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3).

In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE–choroid complex – thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals.