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C2/CFB Complement Genes in progression and severity of Age-Related Macular Degeneration (AMD)

C2/CFB Complement Genes in progression and severity of Age-Related Macular Degeneration (AMD). Brooke Longville Supervised by Prof. Lyle Palmer Prof. Ian Constable Dr. Wayne Greene. What/where is the Macula?. What is AMD?. Late AMD- Neovascular. Early AMD- Exudative Drusen.

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C2/CFB Complement Genes in progression and severity of Age-Related Macular Degeneration (AMD)

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  1. C2/CFB Complement Genes in progression and severity of Age-Related Macular Degeneration (AMD) Brooke Longville Supervised by Prof. Lyle Palmer Prof. Ian Constable Dr. Wayne Greene

  2. What/where is the Macula?

  3. What is AMD? Late AMD- Neovascular Early AMD- Exudative Drusen Late AMD- Atrophic Early AMD- Hard Drusen

  4. AMD is a leading cause of blindness in older caucasians • Distortion/loss of central vision • Symptoms of Early AMD are common • One in eight Early AMD sufferers will progress to Late AMD

  5. Why is AMD Important? • Impact on Society: • Aging Population • Economic Costs • Social Costs • Loss of skilled workers • Burden on family, friends, carers Impact on Individual: • Central Vision • Premature Retirement • Depression, reduced health, reduced quality of life • Social Isolation

  6. About the C2/CFB genes • Adjacent genes on Chromosome 6 • C2 and CFB products perform similar functions in the classical and alternative complement pathways (respectively) • Gold 2006 first discovered association between C2/CFB variants and risk of developing AMD

  7. C2/CFB in the Complement Cascade

  8. Aims • To investigate associations between C2/CFB variants and severity/progression of AMD • In a comprehensively phenotyped cross-sectional case series of 1013 AMD patients (Lions Eye Inst.) • Using a set of 19 haplotype-tagging Single Nucleotide Polymorphisms (SNPs) spanning the genes • Multivariate analyses adjusted for biologically plausible factors and multiple testing

  9. Methods- Population 1013 AMD cases 267 Early AMD 746 Late AMD 71 Atrophic AMD 675 Neovascular AMD

  10. Methods- Data • Genotypic data- 19 haplotype-tagging SNPS across the adjacent C2/CFB genes • pairwise tagging technique • Phenotypic Data • Disease phenotypes • Environmental factors and medical history • Visual acuity measurements • Basic demographics

  11. Methods- Analytical • Univariate and Multivariate statistical analysis of various subphenotypic outcomes • Stepwise regression to construct biologically sensible multivariate models • Binary, ordinal, nominal logistic and linear regressions • Sensitivity tested to check for population stratification • Adjusted for multiple testing

  12. Model Construction Major outcomes: Neovascular AMD • vs Atrophic OR Early • vs Atrophic AND Early Late AMD vs Early AMD Legal Blindness or Low Vision • In Late, Early or all AMD Visual Acuity (in worse eye) Age of Diagnosis Neovascular Lesion Size/ Composition • Major covariates: • Smoking Pack-years and Status • Age at Study • History of CNV treatment • Alcohol Consumption Status • Gender • Ethnicity • Max BMI • NSAID use

  13. Results • D’ = Do the SNPs behave as expected for their relative locations? • R2 = How linked are the SNPs? (Linkage Disequilibrium or LD) • R2 = 1; these variants always inherited together • R2 = 0; these variants never inherited together

  14. Results

  15. Discussion

  16. Summary/Conclusions

  17. Implications of this Research and Future Directions

  18. Acknowledgements

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