Copy number variation in the complement factor H-related genes and age-related macular degeneration

Mol Vis. 2011;17:2080-92. Epub 2011 Aug 6.


Purpose: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apolipoproteins / genetics*
  • Apolipoproteins / metabolism
  • Base Sequence
  • Blood Proteins / genetics*
  • Blood Proteins / metabolism
  • Case-Control Studies
  • Complement C3b Inactivator Proteins / genetics*
  • Complement C3b Inactivator Proteins / metabolism
  • Complement Factor H / metabolism
  • DNA Copy Number Variations*
  • DNA Fingerprinting / methods*
  • DNA Probes / biosynthesis
  • DNA Probes / genetics
  • Eye / metabolism*
  • Eye / pathology
  • Female
  • Gene Dosage*
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Macular Degeneration / genetics*
  • Macular Degeneration / pathology
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Sequence Deletion
  • United States


  • Apolipoproteins
  • Blood Proteins
  • CFHR1 protein, human
  • CFHR3 protein, human
  • CFHR4 protein, human
  • Complement C3b Inactivator Proteins
  • DNA Probes
  • complement factor H, human
  • Complement Factor H