Li R, Nicklas B, Pahor M, Newman A, Sutton-Tyrrell K, Harris T, Lakatta E, Bauer D C, Ding J, Satterfield S, Kritchevsky S B
Department of Preventive Medicine, Center for Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
J Hum Hypertens. 2007 Aug;21(8):673-82. doi: 10.1038/sj.jhh.1002198. Epub 2007 Apr 12.
The role of renin-angiotensin system (RAS) genes on the risk of lower extremity arterial disease (LEAD) in elderly people remains unclear. We assessed the relationship of genetic polymorphisms in RAS: G-6A, T174M and M235T of the angiotensinogen (AGT) gene, and the angiotensin-converting enzyme insertion/deletion (ACE_I/D) variant to the risk of LEAD in the Health, Aging and Body Composition (Health ABC) Study. This analysis included 1228 black and 1306 white men and women whose age ranged between 70 and 79 years at the study enrollment. LEAD was defined as ankle-arm index (AAI) <0.9. Genotype-phenotype associations were estimated by regression analyses with and without adjustment for established cardiovascular disease (CVD) risk factors. The proportion of LEAD was significantly higher in black (21.1%) than that in white elderly people (10.1%, P<0.0001). The distribution of AGT polymorphisms was also significantly different between black and white participants. There was no statistically significant association between the selected RAS genetic variants and LEAD after adjustment for age, antihypertensive medications, lipid-lowering medication, pack-year smoking, body mass index, low-density lipoprotein cholesterol, and prevalent diabetes and coronary heart disease. However, A-T haplotype of G-6A and M235T interacting with homozygous ACE_II (beta=-1.07, P=0.006) and with ACE inhibitors (beta=-1.03, P=0.01) significantly decreased the risk of LEAD in white but not in black participants after adjustment for the selected CVD risk factors. In conclusion, the study observed a gene-gene and gene-drug interaction for LEAD in the white elderly.
肾素-血管紧张素系统（RAS）基因在老年人下肢动脉疾病（LEAD）风险中的作用仍不明确。在健康、衰老与身体成分（Health ABC）研究中，我们评估了RAS中的基因多态性：血管紧张素原（AGT）基因的G-6A、T174M和M235T，以及血管紧张素转换酶插入/缺失（ACE_I/D）变异与LEAD风险的关系。该分析纳入了1228名黑人和1306名白人男性及女性，他们在研究入组时年龄在70至79岁之间。LEAD定义为踝臂指数（AAI）<0.9。通过回归分析估计基因型与表型的关联，分析时对已确定的心血管疾病（CVD）危险因素进行了调整和未调整。黑人中LEAD的比例（21.1%）显著高于老年白人（10.1%，P<0.0001）。黑人和白人参与者之间AGT多态性的分布也存在显著差异。在对年龄、抗高血压药物、降脂药物、吸烟包年数、体重指数、低密度脂蛋白胆固醇以及糖尿病和冠心病患病率进行调整后，所选RAS基因变异与LEAD之间无统计学显著关联。然而，在对所选CVD危险因素进行调整后，G-6A和M235T的A-T单倍型与纯合子ACE_II（β=-1.07，P=0.006）以及与ACE抑制剂（β=-1.03，P=0.01）相互作用，显著降低了白人而非黑人参与者的LEAD风险。总之，该研究观察到老年白人中LEAD存在基因-基因和基因-药物相互作用。
