藥物基因研究學在氣喘治療上的角色

Role of Pharmacogenetics in the Treatment of Asthma

熊得志(Te-Chih Hsiung) ； 羅君禹(Chun-Yu Lo) ； 賴祐德(Yu-Te Lai) ； 黃建達(Chien-Da Huang)

《內科學誌》 20卷2期 (2009/04) Pp. 120-128

https://doi.org/10.6314/JIMT.2009.20(2).03

摘要

氣喘是一種慢性呼吸道炎性反應的疾病。主要治療的藥物，包括急性緩解與長期控制藥物。依據GINA氣喘治療指引，以控制狀態爲基礎的升降階治療原則，大多數的病患多能得到不錯的治療成果，但臨床上仍有少數病患無法達到治療指引定義的控制狀態，其中一項可能的因素是藥物基因變異。乙二型腎上腺受體基因當中有三個主要具編碼的基因多型性(polymorphism)，位在密碼子(codons) 16，27，164。氣喘病人具有密碼子16 同型合子(homozygotes) Arg/Arg基因型，會對短效乙二型擴張劑治療的反應有較差的表現。少數病人會對類固醇的反應較差，產生類固醇抗性，這是因爲在類固醇接受體基因(GR/NR3C1)上產生了突變或基因多型性。相反地，在CRHR1基因變異，則會增加對吸入性類固醇的反應。在ALOX5與LTC4S基因突變的病人對白三烯素調節劑的反應下降。CYP1A2(-2964[G/A])基因多形性，會造成茶醶的清除率下降，可能產生毒性。T 314 allele突變，則會造成組織胺甲基轉換酶(histamine N-methyltransferase)活性降低，減少組織胺分解，進而造成氣管收縮。將藥物基因研究學運用到臨床治療上，最需要的考量是經濟效益。目前藥物基因研究學在臨床上的運用仍不可行。但瞭解氣喘基因多型與治療上的反應差異將可以提供臨床醫師更多治療的方向。因此，當臨床醫師調整氣喘治療藥物組合以期達到症狀與惡化的控制時，這些觀念應銘記在心。

關鍵字

氣喘 ； 藥物基因研究學 ； 基因多型性 ； 治療

並列摘要

Asthma is a chronic inflammatory disease of the airways. Medications for asthma can be divided into two general groups: acute relievers and chronic controllers. The majority of patients with asthma could achieve control by treatment steps as defined by the Global Initiative for Asthma (GINA). However, even treatment fully consistent with current GINA guideline fails to control asthma in some patients. This may be partly due to genetic polymorphisms. There are three major coding polymorphisms of beta-2 adrenoreceptor gene, located in position 16, 27 and 164. Arg/Arg phenotype for codon 16 alters response to treatment and disease severity in patients with asthma. Glucocorticoid resistance in patients with asthma may be due to mutations or polymorphisms in glucocorticoid receptor gene (GR/NR3C1). In contrast, genetic variation in CRHR1 is associated with improved pulmonary function in response to inhaled corticosteroids. Mutations in the promotor region of ALOX5 and LTC4S genes reduce response to leukotriene modifiers. CYP1A2 polymorphism, -2964 (G/A), has been correlated with reduced theophylline clearance and possible toxicity. The T 314 allele for histamine N-methyltransferase results in decreased enzyme activity and possibly also increased bronchoconstriction in asthmatic patients. Economic issues should be considered when applying pharmacogenomics to clinical therapy. It is still not possible to tailor medication for asthma based on pharmacogenomics clinically. However, the impact of genetic variations on response to therapy has the potential to provide physicians more directions of treatment. Thus, when clinicians make modifications of therapeutic regimens for asthma, it is important to keep these concepts in mind.

並列關鍵字

Asthma ； Pharmacogenetics ； Polymorphism ； Treatment