TOKYO—Quitting smoking can reduce the risk of chronic obstructive pulmonary disease (COPD), but because of nicotine dependence, many smokers find it hard to stop permanently. Nicotine is metabolized by CYP2A6, a member of cytochrome P-450. Japanese researchers recently found that a polymorphism of the CYP2A6 gene, CYP2A6del, may keep smokers from quitting, but paradoxically it also protects against emphysema.[1]

STUDYING SMOKERS AND EX-SMOKERS

Genomic DNA was isolated from 203 patients (92 current smokers and 111 ex-smokers) who visited the study hospital for COPD diagnosis or treatment. Cigarette consumption (packs per day) and duration of smoking (years) were calculated. DNA was also obtained from 123 healthy nonsmokers. Both smokers and ex-smokers underwent pulmonary function testing and had computed tomographic (CT) scans of the chest taken.

Two-step polymerase chain reaction and restriction fragment length polymorphism were used to identify the CYP2A6del allele. Those with the *1/*1 genotype were defined as the W (wild type) group, and those with the *1/del or del/del genotypes were defined as the D (deletion) group.

Among current smokers, the number of cigarettes consumed in the D group was significantly lower than that in the W group. Duration of smoking did not differ between genotypes. The percentage of patients having the D allele was significantly lower among heavy smokers than among light smokers, regardless of whether the patients still smoked. The D allele was an independent factor for reduced cigarette consumption but not for duration of smoking.

Paradoxically, though, the presence of the D allele was significantly higher in current smokers than in ex-smokers. The genotype was also found to be an independent inhibitor of smoking cessation.

COPD RISK

The relationship between the CYP2A6del genotype and emphysematous changes on CT scan was also examined. A low attenuation area (LAA) score of 8 on the CT scan indicates that approximately one third of the total lung fields have emphysematous changes; the maximum LAA score, 24, indicates that the entire lung is emphysematous. The presence of the D allele in smokers with an LAA score less than 8 was significantly higher than in smokers whose LAA scores were 8 or higher.

“Our results indicate that having the D allele protects smokers from developing emphysema through a direct effect on the metabolism of substances related to emphysema rather than an indirect effect on the amount of cigarettes smoked,” observed Hidetoshi Nakamura, MD, Department of Medicine at Keio University in Tokyo.

In a logistic regression analysis, the D allele was found to reduce the risk of higher LAA scores and impaired carbon monoxide transfer, but it did not affect the extent of airflow obstruction as determined by forced expiratory volume in one second.

D ALLELE MAKES IT HARDER TO QUIT

These observations are consistent with other studies showing that mutations in CYP2A6 could reduce cigarette consumption, with the D allele limiting the number of cigarettes smoked per day but not lifelong smoking duration. Dr. Nakamura and his research associates postulate that because nicotine is metabolized by CYP2A6, smokers with the D allele have higher levels of nicotine in their blood and, therefore, smoke fewer cigarettes. The current study also showed, however, that the D allele could cause some individuals to become habitual smokers.

“Smokers with the D allele may find it hard to quit smoking, probably due to their enhanced dependence on tobacco,” said Dr. Nakamura. “More efforts may be needed for this group, including closer monitoring and drugs for depression. In addition, lower doses or longer [dosing] intervals may be considered for them [when using] nicotine replacement therapy.”

—Gale Jurasek

Reference
1. Minematsu N, Nakamura H, Iwata M, et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax. 2003;58:623-628.

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