Yi Xingyang, Lin Jing, Wang Chun, Huang Ruyue, Liu Yingying
Department of Neurology, People's Hospital of Deyang City, Deyang, Sichuan, China.
Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Stroke Cerebrovasc Dis. 2017 Aug;26(8):1773-1780. doi: 10.1016/j.jstrokecerebrovasdis.2017.04.005. Epub 2017 May 3.
Eicosanoids are lipid mediators that may play a role in ischemic stroke (IS). However, the association of variants in eicosanoid genes and these interactions with IS risk has not been investigated. The aim of the present study was to investigate the association of 11 variants in eicosanoid genes with IS and to determine whether these gene-gene interactions increase the risk of IS.
Eleven variants in prostaglandin H synthase-1 (PTGS1), PTGS2, thromboxane A2 synthase (TBXAS1), prostacyclin synthase (PTGIS), and prostaglandin E synthase (PTGES) genes were examined using mass spectrometry method in 297 patients with atherothrombotic stroke and 291 controls. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) method. Platelet aggregation and platelet-leukocyte aggregates were measured on admission.
There were no significant differences in the genotype distributions of the 11 variants between patients and controls. However, GMDR analysis showed a significant gene-gene interaction among rs20417, rs5602, and rs41708, which scored 10 for cross-validation consistency and 9 for the sign test (P = .014). Logistic regression analysis showed that high-risk interaction among rs20417, rs5602, and rs41708 was an independent risk factor for atherothrombotic stroke (OR = 2.45, 95% CI: 1.33-3.27, P = .019). The high-risk interactive genotypes were associated with higher platelet aggregation and platelet-leukocyte aggregates.
PTGS2 rs20417, PTGIS rs5602, and TBXAS1 rs41708 three-locus interactions may confer a higher risk for atherothrombotic stroke. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk for IS.
类二十烷酸是脂质介质，可能在缺血性卒中（IS）中发挥作用。然而，类二十烷酸基因变异及其与IS风险的相互作用尚未得到研究。本研究的目的是调查类二十烷酸基因中的11个变异与IS的关联，并确定这些基因-基因相互作用是否会增加IS风险。
采用质谱法检测了297例动脉粥样硬化血栓形成性卒中患者和291例对照者中前列腺素H合酶-1（PTGS1）、PTGS2、血栓素A2合酶（TBXAS1）、前列环素合酶（PTGIS）和前列腺素E合酶（PTGES）基因中的11个变异。使用广义多因素降维（GMDR）方法分析基因-基因相互作用。入院时测量血小板聚集和血小板-白细胞聚集情况。
患者和对照者中11个变异的基因型分布无显著差异。然而，GMDR分析显示rs20417、rs5602和rs41708之间存在显著的基因-基因相互作用，交叉验证一致性得分为10分，符号检验得分为9分（P = 0.014）。逻辑回归分析显示，rs20417、rs5602和rs41708之间的高危相互作用是动脉粥样硬化血栓形成性卒中的独立危险因素（OR = 2.45，95%CI：1.33 - 3.27，P = 0.019）。高危相互作用基因型与较高的血小板聚集和血小板-白细胞聚集相关。
PTGS2 rs20417、PTGIS rs5602和TBXAS1 rs41708三个位点的相互作用可能会增加动脉粥样硬化血栓形成性卒中的风险。本研究中使用的组合分析可能有助于阐明IS的复杂遗传风险。
