Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia.
Ophthalmology. 2013 Aug;120(8):1641-8. doi: 10.1016/j.ophtha.2013.01.014. Epub 2013 Apr 9.
To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD.
Prospective cohort study.
We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.
Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of "as required" injections based on clinician's decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome.
The influence of selected SNPs on mean change in visual acuity (VA) at 12 months.
Mean baseline VA was 51 ± 16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2 ± 14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was -2.9 ± 15.2 letters after 12 months compared with +5.1 ± 14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r(2) = 0.92). None of the other examined SNPs was associated with outcome.
The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients' genotype to achieve optimal treatment response in AMD.
FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.
确定已知与年龄相关性黄斑变性（AMD）风险相关的基因中的遗传变异与新生血管性 AMD 抗血管内皮生长因子（VEGF）治疗的结果之间的关联。
前瞻性队列研究。
我们在澳大利亚皇家维多利亚眼耳医院招募了 224 名连续的新生血管性 AMD 患者。
患者接受了 3 次初始每月雷珠单抗或贝伐单抗注射，然后根据每次随访时根据再治疗标准由临床医生决定的“按需”注射 9 个月。在已知的 AMD 风险相关基因中包括 CFH（rs800292、rs3766404、rs1061170、rs2274700 和 rs393955）、HTRA1（rs11200638）、CFHR1-5（rs10922153、rs16840639、rs6667243 和 rs1853883）、LOC387715/ARMS2（rs3793917 和 rs10490924）、C3（rs2230199 和 rs1047286）、C2（rs547154）、CFB（rs641153）和 F13B（rs6003）在内的 17 个单核苷酸多态性（SNP）进行了检查。使用多变量分析来确定每个 SNP 在治疗结果中的作用。
选定 SNP 对 12 个月时视力（VA）平均变化的影响。
平均基线 VA 为 51±16.8 个早期治疗糖尿病视网膜病变研究字母。总体而言，从基线到 12 个月 VA 的平均变化为+3.2±14.9 个字母。rs11200638-HTRA1 启动子 SNP 的 AA（纯合风险）基因型（P=0.001）和 LOC387715/ARMS2 中的 rs10490924（A69S）的 GG（纯合风险）基因型（P=0.002）在经过多次校正后，与 12 个月时的 VA 结果显著相关。与 AG 或 GG 基因型的患者相比，rs11200638 中 AA 基因型的患者从基线到 12 个月 VA 的平均±标准偏差变化为-2.9±15.2 个字母，而 AG 或 GG 基因型的患者为+5.1±14.1 个字母。这些基因型的患者在 12 个月后也更有可能失去超过 15 个字母。rs11200638 和 rs10490924 高度连锁不平衡（r（2）=0.92）。没有其他检查的 SNP 与结果相关。
HTRA1 启动子 SNP（rs11200638）和 LOC387715/ARMS2 中的 A69S 与新生血管性 AMD 中雷珠单抗或贝伐单抗治疗的视觉结果较差相关，表明与抗 VEGF 治疗存在强烈的药物遗传学关联。这一发现可以帮助根据患者的基因型制定更个体化的治疗方案，以实现 AMD 的最佳治疗反应。
作者没有与本文讨论的任何材料有关的专有或商业利益。
