Research Article: Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking

Date Published: December 27, 2007

Publisher: Public Library of Science

Author(s): Anne E Hughes, Nick Orr, Chris Patterson, Hossein Esfandiary, Ruth Hogg, Vivienne McConnell, Giuliana Silvestri, Usha Chakravarthy, Leif Groop

Abstract: BackgroundAge-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.Methods and FindingsWe genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.ConclusionsAn individual’s risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.

Partial Text: Age-related macular degeneration (AMD) is the most common cause of visual disability in the elderly, and is increasing in prevalence in the Western world as the population ages. In addition to age and smoking, genetic factors play a major role in susceptibility to AMD. There is higher concordance in monozygotic than in dizygotic twins [1], and although there is rarely clear Mendelian inheritance, cases tend to cluster in families [2,3]. The search for susceptibility genes has been performed using linkage studies in AMD families, followed by family-based and case-control association studies. Chromosome 1q31 was first implicated in a linkage study involving a large family [4], and the same region was supported consistently in several genome-wide scans based on analysis of smaller multiplex families [5–13]. Several polymorphisms in CFH, the gene encoding complement factor H, were found to be strongly associated with AMD, and single nucleotide polymorphism (SNP) rs1061170, encoding a nonsynonymous change from tyrosine to histidine at codon 402, was proposed as the main determinant of disease [14–18]. CFH and the closely related genes CFHR3, CFHR1, CFHR4, CFHR2, and CFHR5 are arranged in tandem at the proximal end of a cluster of genes involved in regulation of complement activation. Recently we examined this gene cluster in detail and identified a large deletion that removed both CFHR3 and CFHR1 on a strongly protective haplotype [19].The inhibitory activity of complement factor H is controlled by binding of C-reactive protein (CRP), which increases affinity for C3b and leads to down-regulation of complement activity [20]. There are no known coding polymorphisms in the small CRP gene, but plasma CRP levels are determined by SNPs within its promoter region [21]. Of most significance in persons of European descent is the triallelic (A/C/T) SNP rs3091244, of which the C allele results in lowest plasma CRP levels and the T allele the highest.

Our study assessed the influence of genes in the CFH and LOC387715/HTRA1 regions and smoking status on the etiology of neovascular AMD. We developed a risk model for disease based on comprehensive haplotyping of the genes followed by analysis using logistic regression that also included smoking status. Our model is the first that we know of to take account of haplotypes within the CFH and LOC387715/HTRA1 regions, and allows early identification of those at high risk of developing neovascular AMD in old age. AMD was not inevitable for those in the highest-risk categories, hence exposure to a trigger may be necessary for development of disease.