Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics.
Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics.
复制标题
DOI：
10.1186/1471-2350-12-83
复制
发表时间：
2011-06-17
影响因子：
--
通讯作者：
DeAngelis MM
中科院分区：
文献类型：
--
作者：
Feehan M;Hartman J;Durante R;Morrison MA;Miller JW;Kim IK;DeAngelis MM
在解释显示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））之间的关联的研究中的挑战之一是理解患者群体中关于与病症相关的任何风险因素的表型异质性。当考虑患者对任何开发用于治疗该病症的药物的潜在治疗反应时，这是至关重要的。在本研究中，我们根据AMD和心血管病理学的遗传途径，确定了可能代表治疗开发的几个不同靶点的患者亚型或聚类。我们确定了一个患有新生血管性AMD的患者样本，在以前的研究中，这些患者已被证明通过环境因素（如吸烟）和遗传变异（包括染色体1 q25上的补体因子H基因（CFH）和染色体10 q26上的ARMS 2/HtrA丝氨酸肽酶1（HTRA 1）基因的变异）而具有较高的疾病风险。我们利用现有的流行病学和遗传学数据对其中253例患者进行了多变量分段分析。在多变量模型中，吸烟不能区分患者的亚型。然而，确定了四个有意义的不同患者群，这些患者的心血管健康状况（高胆固醇血症和高血压病史）和ARMS 2/HTRA 1 rs 1049331等位基因的差异最大。这些结果对于试图确定可治疗的新生血管性AMD人群的有效规模的药物开发者具有显著的个性化医学意义。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治疗开发的不同目标，并且开发的可能增加CV风险的治疗对于某些确定的聚类可能是不明智的。
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. 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. 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. 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.
登录
查看更多内容
影响因子：
4
作者：
Baird PN;Hageman GS;Guymer RH
通讯作者：
Guymer RH
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
13.7
作者：
Hogg, Ruth E.;Woodside, Jayne V.;Chakravarthy, Usha
通讯作者：
Chakravarthy, Usha
影响因子：
--
作者：
DeAngelis, MM;Lane, AM;Miller, JW
通讯作者：
Miller, JW
影响因子：
--
作者：
Baker, Michelle L.;Wang, Jie Jin;Rogers, Sophie;Klein, Ronald;Kuller, Lewis H.;Larsen, Emily K.;Wong, Tien Yin
通讯作者：
Wong, Tien Yin