Age-related macular degeneration (AMD) is a complex, late-onset disease that is the leading cause of blindness in the elderly. Age, smoking, and variants in complement factor H (CFH), LOC387715, complement factor B (CFB), and complement component 2 (CC2) are the strongest susceptibility factors for AMD.
CFH inhibits activation of the alternative complement cascade, avoiding injury to self tissues by preventing excessive immune responses. Five CFH-like genes reside nearby on chromosome 1, and likely have similar roles in immune regulation. Deletion of CFHL1 and CFHL3 confers protection from AMD (Hughes et al. 2006). We have confirmed this protective effect (frequency=0.8%, frequency controls=2.6%, p=0.025). However, we also observed a protective haplotype without the deletion (haplotype frequency in cases=12%, controls=21%, p<0.001), suggesting that other protective variants have yet to be identified.
As variants in CFH modify AMD susceptibility, exploration of other genes within the complement cascade is warranted. Variation in adjacent genes CFB and CC2 has been associated with decreased risk(Gold et al. 2006), though subsequent studies were unable to determine whether the effect of CC2 E318D was independent of polymorphisms in CFB or caused by LD between them(Maller et al. 2006). We dissected this region, and confirmed that both loci contribute to decreased risk of AMD, though the effect of CC2 is much smaller than CFB(CC2 E318D p=0.02, CFB R32Q p<0.0001).
The search for novel AMD loci continues. A previous linkage screen identified chromosome 16p12 as a likely location for a novel AMD locus. After increasing SNP density across chr16p12, we combined linkage and association results, gene expression data, and the known biology of genes in the interval to select 4 candidates: CACNG3, HS3ST4, IL4R, and Q7Z6F8. CACNG3 is the strongest candidate (2pt LOD=3.3, haplotypes in family-based and case-control datasets p<0.01, ATA haplotype frequency cases=6.1%, frequency controls=10.3%, p=0.004). A common duplication covers the upstream sequence and first exon of CACNG3, and we hypothesize that this variation may have functional effects that influence susceptibility.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08272007-091444 |
| Date | 27 August 2007 |
| Creators | Spencer, Kylee L. |
| Contributors | Jeffrey A. Canter, Paul Sternberg, David E. McCauley, Douglas P. Mortlock, Jonathan L. Haines |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu//available/etd-08272007-091444/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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