No Clinically Significant Association between CFH and ARMS2 Genotypes and Response to Nutritional Supplements

AREDS Report Number 38

      Objective

      To determine whether genotypes at 2 major loci associated with late age-related macular degeneration (AMD), complement factor H ( CFH) and age-related maculopathy susceptibility 2 ( ARMS2), influence the relative benefits of Age-Related Eye Disease Study (AREDS) supplements.

      Design

      Unplanned retrospective evaluation of a prospective, randomized, placebo-controlled clinical trial of vitamins and minerals for the treatment of AMD.

      Subjects

      AREDS participants (mean age, 69 years) who were at risk of developing late AMD and who were randomized to the 4 arms of AREDS supplement treatment.

      Methods

      Analyses were performed using the Cox proportional hazards model to predict progression to late AMD (neovascular or central geographic atrophy). Statistical models, adjusted for age, gender, smoking status, and baseline AMD severity, were used to examine the influence of genotypes on the response to therapy with 4 randomly assigned arms of AREDS supplement components: placebo, antioxidants (vitamin C, vitamin E, β-carotene), zinc, or a combination.

      Main Outcome Measures

      The influence of the genotype on the relative treatment response to the randomized components of the AREDS supplement, measured as progression to late AMD.

      Results

      Of the 1237 genotyped AREDS participants of white ethnicity, late AMD developed in 385 (31.1%) during the mean follow-up of 6.6 years. As previously demonstrated, CFH genotype ( P = 0.005), ARMS2 ( P< 0.0001), and supplement were associated individually with progression to late AMD. An interaction analysis found no evidence that the relative benefits of AREDS supplementation varied by genotype. Analysis of (1) CFH rs1061170 and rs1410996 combined with ARMS2 rs10490924 with the 4 randomly assigned arms of AREDS supplement and (2) analysis of the combination of CFH rs412852 and rs3766405 with ARMS2 c.372_815del443ins54 with the AREDS components resulted in no interaction ( P = 0.06 and P = 0.45, respectively, before multiplicity adjustment).

      Conclusions

      The AREDS supplements reduced the rate of AMD progression across all genotype groups. Furthermore, the genotypes at the CFH and ARMS2 loci did not statistically significantly alter the benefits of AREDS supplements. Genetic testing remains a valuable research tool, but these analyses suggest it provides no benefits in managing nutritional supplementation for patients at risk of late AMD.

      Abbreviations and Acronyms:

      AMD ( age-related macular degeneration), AREDS ( Age-Related Eye Disease Study), ARMS2 ( age-related maculopathy susceptibility 2), CFH ( complement factor H), df ( degree of freedom), SNP ( single nucleotide polymorphism)
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      References

        • Eye Diseases Prevalence Research Group
        Causes and prevalence of visual impairment among adults in the United States.
        Arch Ophthalmol. 2004; 122: 477-485
        • Age-Related Eye Disease Study Research Group
        A randomized, placebo-controlled clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8.
        Arch Ophthalmol. 2001; 119: 1417-1436
        • Delcourt C.
        • Diaz J.L.
        • Ponton-Sanchez A.
        • Papoz L.
        • POLA Study Group
        Smoking and age-related macular degeneration. The POLA Study.
        Arch Ophthalmol. 1998; 116: 1031-1035
        • Age-Related Eye Disease Study Research Group
        Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19.
        Ophthalmology. 2005; 112: 533-539
        • SanGiovanni J.P.
        • Chew E.Y.
        • Agron E.
        • et al.
        • Age-Related Eye Disease Study Research Group
        The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.
        Arch Ophthalmol. 2008; 126: 1274-1279
        • Age-Related Eye Disease Study Research Group
        The relationship of dietary carotenoid and vitamin A, E, and C with age-related macular degeneration in a case-control study: AREDS report no. 22.
        Arch Ophthalmol. 2007; 125: 1225-1232
        • Seddon J.M.
        • Cote J.
        • Davis N.
        • Rosner B.
        Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio.
        Arch Ophthalmol. 2003; 121: 785-792
        • van Leeuwen R.
        • Ikram M.K.
        • Vingerling J.R.
        • et al.
        Blood pressure, atherosclerosis, and the incidence of age-related maculopathy: the Rotterdam Study.
        Invest Ophthalmol Vis Sci. 2003; 44: 3771-3777
        • Cougnard-Grégoire A.
        • Delyfer M.N.
        • Korobelnik J.F.
        • et al.
        Long-term blood pressure and age-related macular degeneration: the ALIENOR study.
        Invest Ophthalmol Vis Sci. 2013; 54: 1905-1912
        • AMD Gene Consortium
        Seven new loci associated with age-related macular degeneration.
        Nat Genet. 2013; 45: 433-439
        • Westbrook K.
        • Stearns V.
        Pharmacogenomics of breast cancer therapy: an update.
        Pharmacol Ther. 2013; 139: 1-11
        • Emadi A.
        • Karp J.E.
        The clinically relevant pharmacogenomic changes in acute myelogenous leukemia.
        Pharmacogenomics. 2012; 13: 1257-1269
        • Brantley Jr., M.A.
        • Fang A.M.
        • King J.M.
        • et al.
        Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab.
        Ophthalmology. 2007; 114: 2168-2173
        • Lee A.Y.
        • Raya A.K.
        • Kymes S.M.
        • et al.
        Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab.
        Br J Ophthalmol. 2009; 93: 610-613
        • Francis P.J.
        The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: the Lucentis Genotype Study (an American Ophthalmological Society thesis).
        Trans Am Ophthalmol Soc. 2011; 109: 115-156
        • Nischler C.
        • Oberkofler H.
        • Ortner C.
        • et al.
        Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age-related macular degeneration.
        Acta Ophthalmol. 2011; 89 ([report online]): e344-e349
        • Orlin A.
        • Hadley D.
        • Chang W.
        • et al.
        Association between high-risk disease loci and response to anti-vascular endothelial growth factor treatment for wet age-related macular degeneration.
        Retina. 2012; 32: 4-9
        • Hagstrom S.A.
        • Ying G.S.
        • Pauer G.J.
        • et al.
        • Comparison of AMD Treatments Trials Research Group
        Pharmacogenetics for genes associated with age-related macular degeneration in the comparison of AMD treatments.
        Ophthalmology. 2013; 120: 593-599
        • Finger R.P.
        • Wickremasinghe S.S.
        • Baird P.N.
        • Guymer R.H.
        Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration.
        Surv Ophthalmol. 2014; 59: 1-18
        • Klein M.L.
        • Francis P.J.
        • Rosner B.
        • et al.
        CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration.
        Ophthalmology. 2008; 115: 1019-1025
        • Awh C.C.
        • Lane A.M.
        • Hawken S.
        • et al.
        CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration.
        Ophthalmology. 2013; 120: 2317-2323
        • Age-Related Eye Disease Study Research Group
        The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1.
        Control Clin Trials. 1999; 20: 573-600
        • Chen W.
        • Stambolian D.
        • Edwards A.O.
        • et al.
        • Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group
        Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.
        Proc Natl Acad Sci U S A. 2010; 107: 7401-7406
        • 1000 Genomes Project Consortium
        An integrated map of genetic variation from 1,092 human genomes.
        Nature. 2012; 491: 56-65
        • Fritsche L.G.
        • Fariss R.N.
        • Stambolian D.
        • et al.
        Age-related macular degeneration: genetics and biology coming together.
        Annu Rev Genomics Hum Genet. 2014; 15: 151-171

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