Contribution of Copy Number Variation in the Regulation of Complement Activation Locus to Development of Age-Related Macular Degeneration
Katharina E Schmid-Kubista 1,
Nirubol Tosakulwong 1,
Yanhong Wu 2,
Euijung Ryu 3,
Laura A Hecker 1,
Keith Hugh Baratz 1,
William L Brown 1,
and
Albert O. Edwards 4*
1 Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
2 Laboratory Medicine & Pathology, Mayo Clinic, Rochester, Minnesota, United States
3 Biomedical Statistics & Informatics, Mayo Clinic, Rochester, Minnesota, United States
4 Ophthalmology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, United States
* To whom correspondence should be addressed. E-mail: edwardslab{at}mayo.edu.
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Abstract |
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Purpose: To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD).
Methods: A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHR1 in humans. Subjects with (252) and without (249) AMD were genotyped using the assay and the impact on AMD risk evaluated.
Results: The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHR1 in 500 of the 501 samples. Four different combinations of copy number variations were observed with deletion frequencies as follows: both CFHR3 and CFHR1 deletion (14%), CFHR3 only deletion (0.4%), CFHR1 only deletion (1.1%), and CFHR1 duplication (0.1%). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD 8-fold (95% CI, 2-36) and always occurred on a protective haplotype and never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CFHR1 could not be distinguished from the absence of the risk haplotype.
Conclusions: Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the risk haplotype.
Key Words:
age-related macular degeneration, genetic diseases, immunopathology
