title: Copy number variation in the complement factor H-related genes and age-related macular degeneration.
abstract: OBJECTIVE
  To determine the contribution of copy number variation (CNV) in the regulation of complement activation (RCA) locus to the development of age-related macular degeneration (AMD).
  
  
  METHODS
  A multiplex ligation-dependent probe amplification assay was developed to quantify the number of copies of CFH, CFHR3, CFHR1, CFHR4, CFHR2, and CFHR5 in humans. Subjects with (451) and without (362) AMD were genotyped using the assay, and the impact on AMD risk was evaluated.
  
  
  RESULTS
  Eight unique combinations of copy number variation were observed in the 813 subjects. Combined deletion of CFHR3 and CFHR1 was protective (OR=0.47, 95% confidence interval 0.36-0.62) against AMD and was observed in 88 (82 [18.6%] with one deletion, 6 [1.4%] with two deletions) subjects with AMD and 127 (108 [30.7%] with one deletion, 19 [5.4%] with two deletions) subjects without AMD. Other deletions were much less common: CFH intron 1 (n=2), CFH exon 18 (n=2), combined CFH exon 18 and CFHR3 (n=1), CFHR3 (n=2), CFHR1 (n=1), combined CFHR1 and CFHR4 (n=15), and CFHR2 deletion (n=7, 0.9%). The combined CFHR3 and CFHR1 deletion was observed on a common protective haplotype, while the others appeared to have arisen on multiple different haplotypes.
  
  
  CONCLUSIONS
  We found copy number variations of CFHR3, CFHR1, CFHR4, and CFHR2. Combined deletion of CFHR3 and CFHR1 was associated with a decreased risk of developing AMD. Other deletions were not sufficiently common to have a statistically detectable impact on the risk of AMD, and duplications were not observed.
authors.affiliation: Department of Ophthalmology, Ludwig Boltzmann Institute for Retinology and Biomicroscopic Lasersurgery, Rudolf Foundation Clinic, Vienna, Austria. kubista@proeyes.at
authors.forename: Katharina E
authors.initials: KE
authors.lastname: Kubista
authors.forename: Nirubol
authors.initials: N
authors.lastname: Tosakulwong
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Euijung
authors.initials: E
authors.lastname: Ryu
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Roeder
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hecker
authors.forename: Keith H
authors.initials: KH
authors.lastname: Baratz
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.forename: Albert O
authors.initials: AO
authors.lastname: Edwards
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003180:Complement C3b Inactivator Proteins / Q000235:genetics* / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D056915:DNA Copy Number Variations; D016172:DNA Fingerprinting / Q000379:methods*; D015342:DNA Probes / Q000096:biosynthesis / Q000235:genetics; D005123:Eye / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D014481:United States
chemical_list: D001053:Apolipoproteins; D001798:Blood Proteins; C493495:CFH protein, human; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; C105092:CFHR4 protein, human; D003180:Complement C3b Inactivator Proteins; D015342:DNA Probes; D017242:Complement Factor H