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Originally published In Press as doi:10.1167/iovs.09-3975 on June 24, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5070-5079.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3975
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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 H. Baratz,1 William L. Brown,1 and Albert O. Edwards1

From the Departments of 1Ophthalmology, 2Laboratory Medicine and Pathology, and 3Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.

Corresponding author: Albert O. Edwards, Department of Ophthalmology, Ophthalmology Research, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905; edwardslab{at}mayo.edu.

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 (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was 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 CNVs were observed with 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 eightfold (95% CI 2–36) and always occurred on a protective haplotype, 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.






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