A study to be published in the European Respiratory Journal (ERJ) demonstrates that most Japanese smokers' cigarette consumption is conditioned by their genetic heritage. This discovery opens new horizons for stop-smoking treatments.

Nicotine, an alkaloid found in concentrations of 10 to 20 mg per gram of dried tobacco leaf, is known to be the main agent causing cigarette addiction.

However, under the influence of a particular enzyme known to specialists as CYP2A6, nicotine, with its strong effect on the nervous system, can degrade into an inactive substance named cotinine.

The latest data suggest that it is the fall in nicotine levels in the blood and cerebrospinal fluid, caused by the degradation process, that gives rise to the more or less irresistible desire to light another cigarette.

These were the considerations that inspired a Japanese team from Keio University and the Tokyo Electronic Power Company Hospital, led by Hidetoshi Nakamura and Naoto Minematsu, to examine the influence of genetic variations of the enzyme on smoking habits.

For the gene that causes synthesis of the CYP2A6 enzyme can present in various forms, known as alleles, which can be expected to affect nicotine degradation rates and hence the severity of tobacco addiction.

The authors of the study published in February's ERJ decided to focus on the three alleles most commonly found in Asian populations, namely the *4, *7 and *9 forms of the CYP2A6 gene, which slow nicotine degradation to a greater or lesser degree.

The study covered a population of 200 Japanese smokers aged 50 or over, who had smoked the equivalent of at least a pack of cigarettes daily for 10 years and had no particular respiratory disease (other than chronic obstructive pulmonary disease, from which 70 per cent of them suffered).

Three-quarters of Japanese smokers affected

Just over a quarter (26%) of the subjects were found to carry the normal form of the gene (allele *1) on the relevant two chromosomes (homozygotes). In these subjects nicotine degradation is not slowed, and they were found to be the heaviest smokers (almost two packs a day on average).

Conversely, subjects with homozygotic allele *4, who represented 3.5% of the study population, were found to smoke the least on a daily basis (just under one pack a day).

The various combinations of alleles, meanwhile (*1/*9, *1/*7,*1/*4, _ _ *4/*9, *4/*4), give rise to a daily consumption mid-way between the two extremes.

The significance of these data becomes more obvious when one looks at the frequency with which the relevant alleles were found.

"We found a polymorphism for allele *4, *7 or*9 in almost three-quarters of the Japanese subjects", the authors explain. "One could legitimately suppose that the higher nicotine concentrations in these subjects, whose CYP2A6 activity is reduced, make them less likely to light another cigarette."

Most importantly, this study sheds light on the role - previously unknown - of alleles *7 and *9, which are widespread among Asian populations, running at 11% and 20% respectively.

Moreover, the research team believes the results could also give rise to improvements in stop-smoking methods, which consist mainly of nicotine replacement therapies. The data published in the ERJ could thus lead to the development of stop-smoking programmes tailored to the needs (i.e. the genetic profile) of the individual.

"Identification of these polymorphisms should represent the first tangible stage of stop-smoking programmes, in order that nicotine replacement therapies can be adjusted", the authors add.

Finally, it should be noted that, while these data are of direct concern to Asian populations, they have broader significance for the human race.

Allele *9, in particular, is relatively common in certain white populations, including those of Sweden and Turkey, where the results published in February's ERJ could easily be applied.

Title of the original article:
Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms

EUROPEAN RESPIRATORY JOURNAL

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