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Title: Evaluation of new and established age-related macular degeneration susceptibility genes in the Women's Health Initiative Sight Exam (WHI-SE) Study

Author
item PETER, INGA - Mount Sinai School Of Medicine
item HUGGINS, GORDON - Tufts University
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HAAN, MARY - University Of California
item SEDDON, JOHANNA - Tufts University

Submitted to: Journal of Ophthalmology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2011
Publication Date: 12/1/2011
Citation: Peter, I., Huggins, G.S., Ordovas, J.M., Haan, M., Seddon, J.M. 2011. Evaluation of new and established age-related macular degeneration susceptibility genes in the Women's Health Initiative Sight Exam (WHI-SE) Study. Journal of Ophthalmology. 152(6):1005-1013.

Interpretive Summary: Age-related macular degeneration (AMD) is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It is a major cause of blindness and visual impairment in older adults (greater than 50 years). The goal was to assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study. In this study, 146 women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, were assessed. Our analysis showed a protective effect among TT carriers compared with non-carriers for the High Density Lipoprotein (HDL) pathway gene, LIPC rs493258, for intermediate and late AMD. Conversely, other variants in the CFH, ARMS2/HTRA1, and C3 genomic regions were significantly associated with an increased risk of AMD. Moreover, APOE4 carriers at the APOE gene may have a reduced risk of intermediate/late AMD. In summary, in this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease.

Technical Abstract: To assess whether established and newly reported genetic variants, independent of known lifestyle factors, are associated with the risk of age-related macular degeneration (AMD) among women participating in the Women's Health Initiative Sight Exam (WHI-SE) Genetic Ancillary Study. This is a multicenter case-control study. One hundred and forty-six women with intermediate and late stages of AMD and 1269 subjects without AMD underwent ocular examinations and fundus photography to determine stage of AMD. Fourteen polymorphisms at or near 11 genes, including previously confirmed genes CFH, ARMS2/HTRA1, C2, C3, and CFI; recently reported AMD genes in the high-density lipoprotein cholesterol (HDL) pathway LIPC, ABCA1, CETP, and LPL; TIMP3/SYN3, a known ocular gene recently linked with AMD; and APOE, were assessed using logistic regression analysis. RESULTS: After adjustment for demographic, behavioral, and other genetic factors, a protective effect was detected among TT carriers compared with non-carriers for the HDL pathway gene, LIPC rs493258, for intermediate and late AMD (OR [95% confidence interval]: 0.3 [0.2-0.7], P = .003). Variants in CFH rs1410996, ARMS2/HTRA1 A69S, and C3 R102G were significantly associated with an increased risk of AMD. Individuals with the homozygous CFI rs10033900 TT genotype had a 2.9 [1.2-7.2]-fold increased risk, and those with the CFH Y402H GG genotype had a 2.2 [1.0-4.8]-fold higher risk of developing AMD compared with non-carriers. APOE4 carriers may have a reduced risk of intermediate/late AMD (OR = 0.5 [0.3-0.9], P = .015. Suggestive associations were seen between AMD and the HDL pathway genes CETP and LPL. In this unique national cohort of women, we found associations with established AMD-related genetic factors and the recently reported LIPC gene in the HDL pathway. These findings may help develop novel therapeutic targets to treat or delay the onset of the disease.