title: Multilocus analysis of age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case-control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4-4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5-4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.
authors.affiliation: SAIC-Frederick, Basic Science Program, Human Genetics Section, Frederick, MD 21702-1201, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Bergeron-Sawitzke
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: Adam
authors.initials: A
authors.lastname: Olsh
authors.forename: Sarah
authors.initials: S
authors.lastname: Schlotterbeck
authors.forename: Kendal
authors.initials: K
authors.lastname: Lemon
authors.forename: Kala
authors.initials: K
authors.lastname: Visvanathan
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
mesh_terms: D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003175:Complement C2 / Q000235:genetics; D003176:Complement C3 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: C514392:ARMS2 protein, human; D001057:Apolipoproteins E; D003175:Complement C2; D003176:Complement C3; D011506:Proteins; D017242:Complement Factor H; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D011415:Complement Factor B