Human Molecular Genetics Advance Access first published online on June 18, 2007
This version published online on July 10, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm146
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Protective Effect of Complement Factor B and Complement Component 2 Variants in Age-related Macular Degeneration
1 Center for Human Genetics Research, Vanderbilt University, Nashville, TN USA 2 Center for Human Genetics, Duke University, Durham, NC USA 3 Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN USA 4 Duke University Eye Center and Department of Ophthalmology, Duke University Medical Center, Durham, NC USA 5 Institute for Human Genomics, University of Miami, Miami, FL USA
* Corresponding Author: Jonathan L. Haines, Ph.D., Ph: (615) 343-5851, Fax: (615) 343-8619 Email: Jonathan{at}chgr.mc.vanderbilt.edu
Received April 16, 2007; Revised May 1, 2007; Accepted May 1, 2007
Age-related macular degeneration (AMD) is a devastating disorder of the central retina, causing significant visual impairment for 7.5 million elderly Americans. Abnormal regulation of the complement system likely caused by the Y402H polymorphism in the complement factor H gene is a recognized risk factor for AMD, as is the A69S variant in the poorly characterized LOC387715 gene. Recently, polymorphisms in the factor B (CFB) and complement component 2 (CC2) genes were associated with decreased susceptibility to AMD. To validate this association in independent family-based and case-control Caucasian datasets, we genotyped two single nucleotide polymorphisms (SNPs) in CC2 and four SNPs in CFB. The R32Q variant of CFB was significantly associated with protection from AMD in the family-based dataset (p = 0.025). Three SNPs in CC2 and CFB were strongly associated with decreased risk of AMD in the case-control dataset (CC2 E318D p = 0.02, CC2 rs547154 p = 9X10–6, and CFB R32Q p = 2X10–5). The minor alleles at CC2 rs547154 and CFB R32Q are present in 4% of cases vs. 10% of controls, and as these SNPs are in strong linkage disequilibrium (r2 = 0.92), these results likely represent the same protective signal. After controlling for age, Y402H, A69S, and smoking, the effect of CFB R32Q remained quite strong (OR 0.21, 95% confidence interval (0.11 to 0.39) p < 10–4). Likelihood ratio testing and conditional analyses in the case-control dataset suggest that a weaker, independent protective effect exists for CC2 E318D.
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