N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, 3 Gubkin Street, Moscow, 117971, Russia,
Mol Biol Rep. 2013 Nov;40(11):6163-76. doi: 10.1007/s11033-013-2727-8. Epub 2013 Sep 26.
This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.
本研究通过病例对照研究（350 例 CAP 患者，432 例对照）和前瞻性研究，旨在确定解毒/氧化应激和血管重塑途径中功能基因多态性对社区获得性肺炎（CAP）易感性的可能贡献，以及对 CAP 并发症发生的易感性。所有受试者均进行了 14 个基因中的 16 个多态性变异的基因分型，这些基因包括外源性物质解毒 CYP1A1、AhR、GSTM1、GSTT1、ABCB1、氧化还原状态 SOD2、CAT、GCLC 和血管稳态 ACE、AGT、AGTR1、NOS3、MTHFR、VEGFα。单基因座分析中，肺并发症（PC）的风险与 CYP1A1、GCLC 和 AGTR1 基因相关。额外的 PC（中毒性休克综合征和心肌炎）与这些基因无关。我们使用多因素降维法和累积基因风险评分方法评估基因-基因相互作用。最终模型包括 CYP1A1（rs2606345、rs4646903、rs1048943）、GCLC、AGT 和 AGTR1 基因中的>5 个风险等位基因，与胸膜炎、脓胸、急性呼吸窘迫综合征、所有 PC 和急性呼吸衰竭（ARF）相关。我们使用 GeneDecks 中的 Set Distiller 模式考虑 CYP1A1、GCLC、AGT、AGTR1 基因集，通过给定基因集中描述符的共享程度来发现基因集关系。在本研究中，N-乙酰半胱氨酸和氧气被 Set Distiller 定义为与 PC 和 ARF 相关的基因集的最佳描述符。研究结果与文献数据一致，表明遗传决定的氧化应激加重可能导致肺部炎症的进展。
