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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Adult Onset Foveomacular Vitelliform Dystrophy Shows Genetic Overlap With Age-Related Macular Degeneration
Shlomit Jaskoll1,2, Adi Kramer1, Sarah Elbaz-Hayoun1
1Department of Ophthalmology, Hadassah-Hebrew University Medical Center, and the Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Purpose:
Adult-onset foveomacular vitelliform dystrophy (AFVD) shares phenotypic similarities with age-related macular degeneration (AMD). The genetic factors associated with AFVD are unknown in >80% of cases. This study evaluated the association of known AMD genetic risk variants with AFVD and compared systemic complement activation in these conditions.
Methods:
Clinical, imaging, and genetic data were collected from 50 patients with AFVD (men/women = 25/25, mean age ± SD 73 ± 10 years), 917 patients with AMD (men/women = 377/540, mean age ± SD 77 ± 9 years), and 432 unaffected healthy controls (men/women = 202/230, mean age ± SD 71 ± 8 years). Genotyping focused on 52 single nucleotide polymorphisms (SNPs) linked to AMD. Weighted genetic risk scores (GRS) for 19 complement system associated variants, 7 lipid metabolism associated variants, the remaining 26 variants (other pathways GRS), and for all 52 variants (global score) were derived and correlated with phenotype.
Results:
Of the 52 SNPs evaluated, CFH (rs570618) and C2/CFB/SKIV2L (rs116503776 and rs114254831) were associated with AFVD compared with healthy controls (odds ratio [OR] = 2.73, 95% confidence interval [CI] = 1.32-5.73, P = 0.01; OR = 0.31, 95% CI = 0.14-0.71, P = 0.0036; and OR = 0.41, 95% CI = 0.22-0.74, P = 0.0025, respectively). MIR6130/RORB (rs10781182) was negatively associated with AFVD compared with the healthy controls (OR = 0.13, CI = 0.06-0.25, P < 0.0001) and AMD (OR = 0.19, CI = 0.10-0.34, P < 0.0001). Regression analysis showed complement GRS was positively associated with AFVD compared with controls (OR = 1.42, 95% CI = 1.04-1.95, P = 0.03), whereas the other pathways' GRS was negatively associated (OR = 0.46, 95% CI = 0.21-0.98, P = 0.04). AMD was positively associated with the complement score, global score, and ARMS2/HTRA1 compared with controls.
Conclusions:
Non-monogenic AFVD is associated with AMD risk alleles in the complement cascade, but not in other pathways. Further research is needed to explore complement inhibition for AFVD.
