Abstract 17357: A report From the Japanese pharmacogenomics clinical trial; CYP2A6 Gene Polymorphisms Influence Nicotine Dependence and Monoamine Oxidase Gene Polymorphism Does Smoking Cessation Behavior
Backgrounds and Aim: Accumulating evidence has revealed that the genetic polymorphisms could be the risk of the susceptibility to human diseases and the intractableness to the pharmacothearpy. In this study, we performed the pharmacogenomics clinical trial in order to identify the polymorphic mutations that influence the severity of nicotine dependence (ND) and responsiveness to smoking cessation therapies.
Methods and Results: A thousand and sixty six smokers that received nicotine replacement therapy or varenicline according to medical specialists’ prescription were enrolled. The genetic polymorphisms of 50 genes that are related with the nicotine metabolism or the nicotinic neuron functions were determined by PCR-based methods. The relation between the genetic variation and clinical status was statistically analyzed. First, we found that genetic polymorphisms of CYP2A6 (*1, *4, *7, *9) a major nicotine metabolizing enzyme, are closely related with severity of ND. As we reported previously, the subjects with high CYP2A6 activity genotypes, such as *1/*1, *1/*9, *1/*4, *1/*7 and *9/*9, showed the severer ND than those with low activity genotype, such as *4/*4, *4/*7, *4/*9, *7/*7 and *7/*9 (72.9% n=650 vs 50.9% n=234, P <0.001, ODs 2.61, 95%CI 1.91-3.55). Interestingly, in the smokers received varenicline therapy (n=838), the subjects with T allele of the monoamine oxidase A (MAOA) gene polymorphism (rs6323, G/T) exhibit the higher frequency of drug adverse reactions, such as nausea (GT or TT; 41.6% n=401, GG; 29.3% n=437, P <0.001, ODs 1.77, 95%CI 1.29-2.42), decreasing the success rate of smoking cessation therapy (GT or TT; 45.8%, TT; 54.2%).
Conclusion: To our knowledge, this is the first phamacogenomics study that investigates the responsiveness to the pharmacotherapy for smoking cessation. In varenicline therapy, the frequency of the major adverse reactions, nausea, increased in the subjects with T allele of MAOA gene mutation (rs6323), which is known to suppress the expression of the enzyme. As the genetic polymorphisms influence ND and the responsiveness to pharmacotherapy, phamacogenomics test could provide a novel strategy for smoking cessation therapy as a personalized medicine.
- © 2013 by American Heart Association, Inc.