Thompson Miles D, Capra Valerie, Clunes Mark T, Rovati G E, Stankova Jana, Maj Mary C, Duffy David L
Biochemical Genetics and Metabolomics Laboratory, Department of Pediatrics, University of California, San Diego, La JollaCA, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ONCanada.
Department of Health Sciences, San Paolo Hospital, Università degli Studi di Milano Milano, Italy.
Front Pharmacol. 2016 Dec 1;7:299. doi: 10.3389/fphar.2016.00299. eCollection 2016.
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the gene, encoding the Met201Val receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca flux and inositol phosphate generation. In addition, the gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.
本文讨论了与哮喘发病机制及药物治疗反应改变相关的基因变异。许多研究表明，编码负责白三烯合成及通过激活七跨膜结构域受体进行细胞内信号传导的酶的基因存在多态性，如半胱氨酰白三烯1（CYSLTR1）和2（CYSLTR2）受体。白三烯是多不饱和脂氧化二十碳四烯酸，具有广泛的药理和生理作用。在参与白三烯形成的三种酶中，花生四烯酸5脂氧合酶5（ALOX5）、白三烯C4合酶（LTC4S）和白三烯水解酶（LTA4H）均具有多态性。这些多态性常导致半胱氨酰白三烯（CysLTs，即LTC4、LTD4和LTE4）和白三烯B4（LTB4）的产生量可变。位于该基因启动子区域Sp1结合基序内的可变数目串联重复序列与白三烯负荷及支气管收缩相关，且与哮喘风险无关。该基因中的一个444A>C单核苷酸多态性（SNP），其编码一种在花生四烯酸主链C-6位形成谷胱甘肽加合物所需的酶，与严重哮喘及对半胱氨酰白三烯1受体拮抗剂扎鲁司特的反应改变有关。CysLT途径中的基因变异性可能对药物反应改变产生累加或协同作用。该基因的601A>G变异体，编码Met201Val受体变异体，在欧洲普通人群中与特应性哮喘相关，其出现频率约为2.6%。该变异最初在南大西洋偏远岛屿特里斯坦 - 达库尼亚的奠基人群中发现，该人群中特应性疾病患病率约为45%，哮喘患病率为36%。研究表明，与特应性相关的Met201Val变异体在配体结合、钙通量和肌醇磷酸生成方面具有失活作用。此外，位于Xq13 - 21.1的该基因与特应性哮喘有关。文中还讨论了激活型Gly300Ser CYSLTR1变异体。除了基因位点外，哮喘风险可能还受吸烟等环境因素影响。本文在已知影响哮喘的其他基因和环境因素背景下，讨论了CysLT途径基因序列变异对特应性哮喘的影响。
