CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration

Abstract

In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility.Age-related macular degeneration (AMD; OMIM 603075) is a complex degenerative disorder that primarily affects the elderly. Disease susceptibility is influenced by multiple genetic 1-5 and environmental factors 6-9 . Recently, targeted and genome-wide searches have identified alleles on chromosomes 1q and 10q that are strongly associated with disease susceptibility 10-14 . In each case, the association seems to be robust and has been replicated in multiple samples. We previously showed that the Y402H-encoding variant of CFH is strongly associated with AMD susceptibility in a sample of affected individuals and controls Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ Note: Supplementary information is available on the Nature Genetics website. After quality assessment of genotype data (see Methods), we tested each SNP for association in 544 unrelated affected individuals and 268 unrelated controls (Fig. 1). As expected, we observed strong association between disease status and the Y402H-encoding variant previously associated with AMD in multiple studies (likelihood ratio test χ 2 = 110.05, P <10 −25 ). Unexpectedly, 20 other variants showed even stronger association. The strongly associated SNPs fell into two linkage disequilibrium (LD) groups (colored in purple and green in Fig. 1), such that, within each group, pairwise r 2 > 0.80, and between groups, pairwise r 2 < 0.50. The Y402H-encoding variant was included in one of the LD groups (the purple group in Fig. 1). The three SNPs showing strongest association are a synonymous SNP in exon 10, rs2274700 (LRT χ 2 = 135.42, P < 10 −30 ) and two intronic SNPs, rs1410996 (LRT χ 2 = 132.70, P < 10 −29 ) and rs7535263 (LRT χ 2 = 130.43, P < 10 −29 ). We observed similar results using a family-based association test 16,17 that incorporated all 726 affected individuals genotyped. Table 1 summarizes results of family-based and case-control single-SNP association tests for rs1061170 (the Y40...

Vascular endothelial growth factor in eye disease

“…In addition, analyses of human blood for indicators of inflammation, such as C-reactive protein and white blood cell count, showed associations of inflammation with AMD (Seddon et al, 2004;Despriet et al, 2006;Shankar et al, 2007). Finally, a common polymorphism in the complement regulatory protein, complement factor H (CFH) (Tyr402His), was found to be strongly associated with increased risk of AMD, providing further evidence supporting inflammation in AMD (Klein et al, 2005;Maller et al, 2006;Li et al, 2006b;Haines et al, 2005;Edwards et al, 2005;Rivera et al, 2005).…”

“…AMD develops late in life, yet is strongly associated with certain common genetic mutations (Klein et al, 2005;Maller et al, 2006;Li et al, 2006b;Haines et al, 2005;Edwards et al, 2005;Rivera et al, 2005). Evidence supports that both genetic and environmental factors play a role in the pathogenesis (Seddon et al, 2006b).…”

CRISPLD2: a novel NSCLP candidate gene

“…It is unknown whether rs2326398, which is not a splice site or in a coding region, might cause a functional change in the protein (43,44). Intronic SNPs have been shown to be associated with other complex diseases, such as IRF6 with NSCLP, RET (RET proto-oncogene) with Hirschsprung disease and CFH (complement factor H) with age-related macular degeneration (13,14,16,(45)(46)(47). Together, this suggests that common genetic variation in non-coding regions may be important and should not be overlooked in complex human diseases.…”

Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD)

“…Recent progress in AMD genetics has established several important risk loci, among them the complement factor H (CFH) on chromosome 1 (1q31) (Edwards et al 2005;Hageman et al 2005Hageman et al , 2006Hughes et al 2006;Klein et al 2005;Li et al 2006) and the age-related maculopathy susceptibility 2 (ARMS2/HTRA1) on chromosome 10 (10q26) (Dewan et al 2006;Jakobsdottir et al 2005;Rivera et al 2005;Schmidt et al 2006;Tanimoto et al 2007;Weger et al 2007;Yang et al 2006). Both loci combined are thought to account for more than 50 % of AMD cases (Edwards et al 2005;Klein et al 2005;Maller et al 2006;Swaroop et al 2007;Thakkinstian et al 2006).…”