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Originally published In Press as doi:10.1167/iovs.08-3231 on February 21, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:3386-3393.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3231
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Complement Component 3 (C3) Haplotypes and Risk of Advanced Age-Related Macular Degeneration

Kyu Hyung Park,1,2 Brooke L. Fridley,3 Euijung Ryu,3 Nirubol Tosakulwong,1 and Albert O. Edwards1

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

PURPOSE. Nonsynonymous coding single nucleotide polymorphisms (nsSNPs) in complement component 3 (C3) alter the risk of age-related macular degeneration (AMD). This was a study of the effect of haplotypes across C3 on AMD risk.

METHODS. Nine SNPs tagging haplotypes across C3 were genotyped on 738 subjects at the Mayo Clinic. Haplotype analyses were performed with and without conditioning on individual SNPs. Replication studies were performed using 1541 subjects from the age-related eye disease study (AREDS).

RESULTS. Two nsSNPs located 5125 bp apart in the 5' end of C3 showed the highest association (rs1047286 or P314L, P = 9.2E-05; rs2230199 or R102G, P = 4.1E-05) with AMD. The minor alleles of both SNPs tagged a single risk haplotype. The effects of the two nsSNPs could not be distinguished due to high linkage disequilibrium. The risk SNPs preferentially promoted the development of advanced AMD relative to early AMD in both the Mayo and AREDS subjects. Haplotypes in the 3' end of the C3 locus were associated with AMD in both the Mayo and AREDS subjects. The effect persisted after conditioning on the nsSNPs only in the Mayo subjects. No interaction was found between rs2230199 and smoking or other AMD loci.

CONCLUSIONS. nsSNPs in C3 increased the risk of developing AMD 1.8-fold for 1 risk allele or 2.4-fold for two risk alleles and were preferentially associated with advanced AMD. Further study is needed to determine whether haplotypes in the 3' end of C3 have an independent association with AMD.




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K. E. Schmid-Kubista, N. Tosakulwong, Y. Wu, E. Ryu, L. A. Hecker, K. H. Baratz, W. L. Brown, and A. O. Edwards
Contribution of Copy Number Variation in the Regulation of Complement Activation Locus to Development of Age-Related Macular Degeneration
Invest. Ophthalmol. Vis. Sci., November 1, 2009; 50(11): 5070 - 5079.
[Abstract] [Full Text] [PDF]


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