Complement Factor H Polymorphism in Age- Related Macular Degeneration* *Klein RJ, et al. Science. 2005; 308:

Overview Introduction Methods Results Discussion 2

Age-Related Macular Degeneration (AMD) Leading cause of blindness in elderly Gradual destruction of central field vision Key feature is drusen Risk factors 3

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Methods Whole-genome case-control association study Subset of Age-Related Eye Disease Study N=146: 96 cases, 50 controls All were genotyped Bonferroni correction 5

Allelic Associations 103, 611 SNPS analyzed 2 SNPS, rs & rs , significant rs out of Hardy-Weinberg equilibrium & no longer significant Selection of another SNP: rs

Figure 1 7

Table 1 Attributers (C/G)rs (C/T) Risk alleleCC Allelic association χ 2 nominal P value4.1 × 10 −8 1.4 × 10 −6 Odds ratio (dominant) (95% CI)4.6 (2.0–11)4.7 (1.0–22) PAR (95% CI)70% (42–84%)80% (0–96%) Frequency in HapMap CEU Odds ratio (recessive) (95% CI)7.4 (2.9–19)6.2 (2.9–13) PAR (95% CI)46% (31–57%)61% (43–73%) Frequency in HapMap CEU

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Candidate markers Identified N1 haplotype with highest risk Re-sequenced exons of 96 participants Found SNP in exon 9 of CFH w/ tyrosine- histidine change 10

11 Discussion Linkage scans associate CFH w/ AMD C5b-9 complex found in drusen Immunofluorescence confirms CFH in eyes w/ AMD

12 Conclusion Age & smoking affect plasma levels of CFH Histidine variant almost always occurs in AMD Additional studies to examine tyrosine- histidine role in AMD

References Facts about age-related macular degeneration, NEI, National Institute of Health, gen/armd_facts.asp. Podgor MJ, Leske MC, Ederer F. Incidence estimates for lens changes, macular changes, open-angle glaucoma and diabetic retinopathy. Am J Epidemiol. 1983;118:

Figure 3 14