title: Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.
abstract: It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Morad
authors.initials: M
authors.lastname: Ansari
authors.forename: Paul M
authors.initials: PM
authors.lastname: McKeigue
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Armbrecht
authors.forename: John R W
authors.initials: JR
authors.lastname: Yates
authors.forename: Zoran
authors.initials: Z
authors.lastname: Vatavuk
authors.forename: Goran
authors.initials: G
authors.lastname: Bencic
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolcic
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Van Duijn
authors.forename: Susan
authors.initials: S
authors.lastname: Campbell
authors.forename: Chloe M
authors.initials: CM
authors.lastname: Stanton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huffman
authors.forename: Xinhua
authors.initials: X
authors.lastname: Shu
authors.forename: Jane C
authors.initials: JC
authors.lastname: Khan
authors.forename: Humma
authors.initials: H
authors.lastname: Shahid
authors.forename: Simon P
authors.initials: SP
authors.lastname: Harding
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Baljean
authors.initials: B
authors.lastname: Dhillon
authors.forename: Pavao
authors.initials: P
authors.lastname: Rudan
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sim
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
mesh_terms: D000483:Alleles; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003180:Complement C3b Inactivator Proteins / Q000235:genetics* / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007438:Introns; D008268:Macular Degeneration / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H