Dept. of Pharmacology & Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands.
BMC Cardiovasc Disord. 2010 Jun 2;10:23. doi: 10.1186/1471-2261-10-23.
Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype.
Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates.
Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations.
We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.
基因-表型关联研究通常基于单个基因内的多个多态性或单倍型组成的多态性。有人提出，不同基因中影响同一表型的多态性组合，可能比单个基因内的多态性组合具有更强的表型关联。我们使用编码肾素-血管紧张素-醛固酮系统和高血压表型成分的基因来检验这一假设。
我们的分析基于从阿姆斯特丹人口登记处随机抽取的横断面 SUNSET 研究的 1379 名参与者。每个受试者均接受血管紧张素原 M235T、血管紧张素转换酶插入/缺失和血管紧张素 II 型 1 受体 A1166C 多态性的基因分型。高血压表型定义为分类变量，将高血压与大多数先前研究中的正常血压进行比较，或使用收缩压、舒张压和平均血压在多元回归分析中作为连续变量，性别、种族、年龄、体重指数和抗高血压药物作为协变量。
在孤立的多态性和双多态性和三多态性组合中，研究了每个多态性的基因型-表型关系。在单多态性水平上，只有血管紧张素 II 型 1 受体的 A 等位基因与高血压表型相关。使用两个或所有三个基因的多态性组合并没有产生更强/更一致的关联。
我们得出结论，至少就肾素-血管紧张素-醛固酮系统和高血压表型而言，多个基因的生理相关多态性组合不一定在分析基因型/表型关联方面提供额外的益处。
