Liu Ruoshan, Zhao Hongye, Wang Yuefei, Wang Yanli, Lu Changzhu, Xiao Yu, Jia Nan, Wang Bin, Niu Wenquan
Department of Anesthesiology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Physiology, Qiqihar Medical University, Qiqihar, Heilongjiang, China.
PLoS One. 2014 Jan 20;9(1):e86095. doi: 10.1371/journal.pone.0086095. eCollection 2014.
Via direct sequencing, we have recently identified six common polymorphisms in angiotensin receptor-like 1 (AGTRL1) gene, and found only two polymorphisms were significantly associated with hypertension in a family-based analysis on 1,015 southern Han Chinese. Extending our previous work and considering the ubiquity of epistasis in determining disease susceptibility, we, in this study, sought to explore the potential interaction of AGTRL1 gene six polymorphisms with hypertension in a large northeastern Han Chinese population.
This was a case-control study involving 1,009 sporadic hypertensive patients and 756 normotensive controls. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. The genotypes and alleles of rs7119675 and rs11544374 differed significantly between the two groups (P<0.0005), even after the Bonferroni correction. Under three genetic models, significant association was consistently observed for rs7119675 and rs11544374, and this association was independent of confounding factors. Taking rs7119375 as an example, the odds of having hypertension was 2.46 (95% confidence interval (95% CI): 2.06-2.94), 2.82 (95% CI: 2.29-3.46) and 3.97 (95% CI: 2.37-6.64) under additive, dominant and recessive models (P<0.001), respectively, whereas the adjusted risk estimates were slightly attenuated but still significant. The frequencies of most derived haplotypes differed significantly between patients and controls. Haplotype-phenotype analyses indicated marginal association for triglyceride (P(Sim) = 0.011) and total cholesterol (P(Sim) = 0.025) in patients and for triglyceride in controls (P(Sim) = 0.023). The overall best MDR model included rs11544374, rs7119375 and rs948847 with the maximal testing accuracy of 0.737 and cross-validation consistency of 10 out of 10 (P<0.0001). Further interaction entropy graph suggested that the interaction of rs7119375 with rs11544374 and rs948847 was strongly antagonized.
Our findings demonstrate that AGTRL1 genetic polymorphisms might contribute to the development of hypertension independently and/or through complex interaction.
通过直接测序，我们最近在血管紧张素受体样1（AGTRL1）基因中鉴定出6种常见多态性，并在对1015名中国南方汉族人群进行的基于家系的分析中发现只有2种多态性与高血压显著相关。扩展我们之前的研究工作，并考虑到上位性在决定疾病易感性方面的普遍性，我们在本研究中试图在一个大型中国东北汉族人群中探索AGTRL1基因6种多态性与高血压之间的潜在相互作用。
这是一项病例对照研究，涉及1009例散发性高血压患者和756例血压正常对照者。数据采用Haplo.Stats和多因素降维（MDR）软件进行分析。所有多态性均符合哈迪-温伯格平衡。即使经过Bonferroni校正，两组之间rs7119675和rs11544374的基因型和等位基因仍存在显著差异（P<0.0005）。在三种遗传模型下，rs7119675和rs11544374均始终显示出显著关联，且这种关联独立于混杂因素。以rs7119375为例，在加性、显性和隐性模型下，患高血压的比值比分别为2.46（95%置信区间（95%CI）：2.06 - 2.94）、2.82（95%CI：2.29 - 3.46）和3.97（95%CI：2.37 - 6.64）（P<0.001），而校正后的风险估计值虽略有减弱但仍具有显著性。大多数衍生单倍型的频率在患者和对照者之间存在显著差异。单倍型 - 表型分析表明，患者的甘油三酯（P(Sim) = 0.011）和总胆固醇（P(Sim) = 0.025）以及对照者的甘油三酯（P(Sim) = 0.023）存在边缘关联。总体最佳的MDR模型包括rs11544374、rs7119375和rs948847，最大检验准确性为0.737，交叉验证一致性为10/10（P<0.0001）。进一步的相互作用熵图表明，rs7119375与rs11544374和rs948847之间的相互作用具有强烈的拮抗作用。
我们的研究结果表明，AGTRL1基因多态性可能独立地和/或通过复杂的相互作用导致高血压的发生。
