通过基因和心血管风险特征鉴定新生血管性年龄相关性黄斑变性患者的亚型。
Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics.
机构信息
Ocular Molecular Genetics Institute and the Retina Service, Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA.
出版信息
BMC Med Genet. 2011 Jun 17;12:83. doi: 10.1186/1471-2350-12-83.
BACKGROUND
One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology.
METHODS
We identified a sample of patients with neovascular AMD, that in previous studies had been shown to be at elevated risk for the disease through environmental factors such as cigarette smoking and genetic variants including the complement factor H gene (CFH) on chromosome 1q25 and variants in the ARMS2/HtrA serine peptidase 1 (HTRA1) gene(s) on chromosome 10q26. We conducted a multivariate segmentation analysis of 253 of these patients utilizing available epidemiologic and genetic data.
RESULTS
In a multivariate model, cigarette smoking failed to differentiate subtypes of patients. However, four meaningfully distinct clusters of patients were identified that were most strongly differentiated by their cardiovascular health status (histories of hypercholesterolemia and hypertension), and the alleles of ARMS2/HTRA1 rs1049331.
CONCLUSIONS
These results have significant personalized medicine implications for drug developers attempting to determine the effective size of the treatable neovascular AMD population. Patient subtypes or clusters may represent different targets for therapeutic development based on genetic pathways in AMD and cardiovascular pathology, and treatments developed that may elevate CV risk, may be ill advised for certain of the clusters identified.
背景
在解释将环境和基因型数据与疾病结果（如新生血管性年龄相关性黄斑变性（AMD））相关联的研究时，面临的挑战之一是了解与疾病相关的任何风险因素的患者人群内的表型异质性。当考虑到任何开发用于治疗该疾病的药物的患者的潜在治疗反应时，这一点至关重要。在本研究中，我们根据 AMD 和心血管病理学中的遗传途径，确定了患者亚型或聚类，这些亚型或聚类可能代表了几种不同的治疗开发目标。
方法
我们鉴定了患有新生血管性 AMD 的患者样本，在以前的研究中，通过环境因素（例如吸烟）和遗传变异（包括染色体 1q25 上的补体因子 H 基因（CFH）和染色体 10q26 上的 ARMS2/HtrA 丝氨酸肽酶 1（HTRA1）基因中的变异）表明这些患者患有该疾病的风险增加。我们利用可用的流行病学和遗传数据对这 253 名患者进行了多元分割分析。
结果
在多元模型中，吸烟无法区分患者的亚型。但是，我们确定了四个意义重大的患者聚类，这些聚类最能通过其心血管健康状况（高胆固醇血症和高血压病史）以及 ARMS2/HTRA1 rs1049331 的等位基因来区分。
结论
这些结果对于试图确定可治疗的新生血管性 AMD 人群的有效治疗规模的药物开发者具有重要的个性化医学意义。基于 AMD 和心血管病理学中的遗传途径，患者亚型或聚类可能代表不同的治疗开发目标，而开发出的可能会增加心血管风险的治疗方法，可能不适合确定的某些聚类。
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