Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype

Centre for Clinical Pharmacology, Department of Medicine, University College London, London, UK.
International Journal of Epidemiology (Impact Factor: 9.18). 01/2012; 41(1):250-62. DOI: 10.1093/ije/dyr204
Source: PubMed


Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry.
In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

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    • "Age-related macular degeneration (AMD) is the leading cause of blindness and visual impairment in developed countries and its prevalence is likely to increase over time, given the ageing population [1]. There is an increasing body of genetic [2,3,4,5,6] and biochemical [7] evidence that AMD is a disease of complement dysregulation, and therefore, that the innate immune system has a key role in the pathogenesis of the disease. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in developed nations and has been associated with complement dysregulation in the central retina. The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD and is present in approximately 30% of people of European descent. CFH, in conjunction with other factors, regulates complement activation in host tissues, and the Y402H polymorphism has been found to alter the protein's specificity for heparan sulphate (HS) - a complex polysaccharide found ubiquitously in mammals. HS, which is present on the cell surface and also in the extracellular matrix, exhibits huge structural diversity due to variations in the level/pattern of sulphation, where particular structures may act as 'ZIP codes' for different tissue/cellular locations. Recent work has demonstrated that CFH contains two HS-binding domains that each recognize specific HS ZIP codes, allowing differential recognition of Bruch's membrane (in the eye) or the glomerular basement membrane (in the kidney). Importantly, the Y402H polymorphism impairs the binding of CFH to the HS in Bruch's membrane, which could result in increased complement activation and chronic local inflammation (in 402H individuals) and thereby contribute to AMD pathology. © 2013 S. Karger AG, Basel.
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    • "The hugely mounting number of scientific reports regarding AMD-related gene variants counteracts the chance to get any unequivocal interpretation of these correlative data. In this complex scenario, which has built up more than ever in the last five years, several genes seem to be the most attractive in playing remarkable roles in different steps of AMD pathogenesis [24–37]. "
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    • "Those that decrease function of the pathway are protective, and those that increase function create risk. Moreover, the variants have both independent and additive effects on the risk of developing AMD [25] [47] [48] [52] [58]. Other inhibitors of the AP include membrane cofactor protein (MCP; CD46), decay accelerating factor (DAF; CD55), and complement receptor one (CR1; CD35, the C3b/C4b or immune adherence receptor). "
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    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries; with the aging population, the negative health impacts and costs of the disease will increase dramatically over the next decade. Although the exact cause of AMD is unknown, genetic studies have implicated the complement system as well as other immune responses in disease pathogenesis and severity. Furthermore, histologic studies have shown the presence of macrophages, lymphocytes, and mast cells, as well as fibroblasts, in both atrophic lesions and with retinal neovascularization. This review summarizes discussions from the fifth annual conference of the Arnold and Mabel Beckman Initiative for Macular Research by the Inflammation and Immune Response Task Force. These deliberations focused on the role of inflammatory immune responses, including complement, inflammasomes, adaptive immune responses, and para-inflammation, unanswered questions and studies to address these questions, and potential immune-related therapeutic targets for AMD.
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