CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration
CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration
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DOI：
10.1016/j.ophtha.2013.07.039
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发表时间：
2013-11-01
期刊：
影响因子：
13.7
通讯作者：
Kim, Ivana K.
中科院分区：
文献类型：
--
作者：
Awh, Carl C.;Lane, Anne-Marie;Kim, Ivana K.
目标：老年性黄斑变性相关眼病研究（AREDS）表明，抗氧化剂和锌补充剂可降低中重度老年性黄斑变性（AMD）患者的进展。设计：随机前瞻性临床试验的遗传学分析。参与者：白色患者，1只眼睛患有AREDS 3类AMD，另一只眼睛患有AREDS 1 - 4类AMD，参加AREDS，并有可用的外周血来源DNA（995）。评估受试者的已知AMD遗传风险标志物和治疗类别。采用考克斯regression.Main Outcome Measures：The effect of inherited gene polymorphisms on treatment groupespecific rate of progression to advanced AMD.Results：平均10.1年以上，具有1或2个补体因子H（CFH）风险等位基因的个体从单独抗氧化剂中获得最大益处。在这些患者中，添加锌否定了抗氧化剂的益处。与无CFH危险等位基因的患者相比，锌和抗氧化剂治疗与2个CFH危险等位基因的风险比（RR）为1.83相关（P=1.03E-02）。年龄相关性黄斑病变敏感性2（ARMS 2）风险等位基因的患者从含锌方案中获得最大益处，在ARMS 2风险等位基因存在的情况下对抗氧化剂产生有害反应。与无ARMS 2风险等位基因的患者相比，抗氧化剂治疗与具有1个ARMS 2风险等位基因的患者的RR为2.58和具有2个ARMS 2风险等位基因的患者的RR为3.96相关（P 1.04E-6）。CFH和ARMS 2风险等位基因纯合子的个体没有从任何类别的AREDS treatment.Conclusions：中度AMD患者可以受益于营养补充剂的药物基因组学选择。在这项分析中，没有CFH风险等位基因和有1或2个ARMS 2风险等位基因的患者从仅补充锌中获得最大益处。具有一个或两个CFH风险等位基因且无ARMS 2风险等位基因的患者从仅补充抗氧化剂中获得最大益处;锌治疗与进展为晚期AMD的增加相关。这些建议可以通过基因型导向治疗改善预后。(C)2013年由美国眼科学会。
Objective: The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD.Design: Genetic analysis of a randomized, prospective clinical trial.Participants: White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995).Methods: Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression.Main Outcome Measures: The effect of inherited gene polymorphisms on treatment groupespecific rate of progression to advanced AMD.Results: Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P=1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment.Conclusions: Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy. (C) 2013 by the American Academy of Ophthalmology.