Pillai Sreekumar G, Cousens Diane J, Barnes Ashley A, Buckley Peter T, Chiano Mathias N, Hosking Louise K, Cameron Lee-Ann, Fling Mary E, Foley James J, Green Andrew, Sarau Henry M, Schmidt Dulcie B, Sprankle Catherine S, Blumenthal Malcolm N, Vestbo Jorgen, Kennedy-Wilson Karen, Wixted William E, Wagner Michael J, Anderson Wayne H, Ignar Diane M
Genetics Research, GlaxoSmithKline Research Triangle Park, NC, USA.
Pharmacogenetics. 2004 Sep;14(9):627-33. doi: 10.1097/00008571-200409000-00007.
Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2. The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists. In this report, we investigated a possible role for therapeutic modulation of CYSLTR2 in asthma by investigating genetic association with asthma and further characterization of the pharmacology of a coding polymorphism.
The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network).
A significant association of the coding polymorphism, 601A>G, with asthma was observed (P = 0.003). We replicated these findings in a collection of 384 families from the Genetics of Asthma International Network (P = 0.04). The G allele is significantly under-transmitted to asthmatics, indicating a possible role for this receptor in resistance to asthma. The potency of cysteinyl leukotrienes at the wild-type CYSLTR2 and the coding polymorphism 601A>G were assessed using a calcium mobilization assay. The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2.
Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.
半胱氨酰白三烯（CYSLTR）是哮喘病理生理学中的强效生物介质，已鉴定出两种受体，即CYSLTR1和CYSLTR2。目前用于控制哮喘患者支气管收缩和炎症的白三烯调节剂是CYSLTR1特异性白三烯受体拮抗剂。在本报告中，我们通过研究与哮喘的基因关联以及对编码多态性药理学的进一步表征，探讨了CYSLTR2治疗性调节在哮喘中的可能作用。
通过传递不平衡检验，在两个基于家系的样本中评估CYSLTR2多态性与哮喘的关联（来自丹麦和美国明尼苏达州的359个家系以及来自国际哮喘遗传学网络的384个家系）。
观察到编码多态性601A>G与哮喘存在显著关联（P = 0.003）。我们在来自国际哮喘遗传学网络的384个家系样本中重复了这些发现（P = 0.04）。G等位基因向哮喘患者的传递显著不足，表明该受体在哮喘抵抗中可能起作用。使用钙动员试验评估了野生型CYSLTR2和编码多态性601A>G时半胱氨酰白三烯的效力。两种形式的受体对LTC4和LTE4的效力相似，LTB4无活性，然而，与野生型CYSLTR2相比，LTD4在601A>G时的效力约低五倍。
由于601A>G改变了LTD4的效力，且该变异等位基因可能与哮喘抵抗相关，因此调节CYSLTR2可能对哮喘药物治疗有用。
