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Title page for ETD etd-08272007-091444


Type of Document Dissertation
Author Spencer, Kylee L.
URN etd-08272007-091444
Title Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility
Degree PhD
Department Human Genetics
Advisory Committee
Advisor Name Title
Douglas P. Mortlock Committee Chair
David E. McCauley Committee Member
Jeffrey A. Canter Committee Member
Jonathan L. Haines Committee Member
Paul Sternberg Committee Member
Keywords
  • complex genetic disease
Date of Defense 2007-08-16
Availability unrestricted
Abstract
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.

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