CYP2A6 reduced activity gene variants confer reduction in lung cancer risk in African American smokers—findings from two independent populations

Abstract

We investigated genetic variation in CYP2A6 in relation to lung cancer risk among African American smokers, a high-risk population. Previously, we found that CYP2A6, a nicotine/nitrosamine metabolism gene, was associated with lung cancer risk in European Americans, but smoking habits, lung cancer risk and CYP2A6 gene variants differ significantly between European and African ancestry populations. Herein, African American ever-smokers, drawn from two independent lung cancer case-control studies, were genotyped for reduced activity CYP2A6 alleles and grouped by predicted metabolic activity. Lung cancer risk in the Southern Community Cohort Study (n = 494) was lower among CYP2A6 reduced versus normal metabolizers, as estimated by multivariate conditional logistic regression [odds ratio (OR) = 0.44; 95% confidence interval (CI) = 0.26-0.73] and by unconditional logistic regression (OR = 0.62; 95% CI = 0.41-0.94). The association was replicated in an independent study from MD Anderson Cancer Center (n = 407) (OR = 0.64; 95% CI = 0.42-0.98), and pooling the studies yielded an OR of 0.64 (95% CI = 0.48-0.86). Exploratory analyses revealed a significant interaction between CYP2A6 genotype and sex on the risk for lung cancer (Southern Community Cohort Study: P = 0.04; MD Anderson: P = 0.03; Pooled studies: P = 0.002) with a CYP2A6 effect in men only. These findings support a contribution of genetic variation in CYP2A6 to lung cancer risk among African American smokers, particularly men, whereby CYP2A6 genotypes associated with reduced metabolic activity confer a lower risk of developing lung cancer.

CYP2A6 genetic polymorphism is associated with decreased susceptibility to squamous cell lung cancer in Japanese smokers

“…Tan et al suggested that CYP2A6 gene deletion increased lung cancer risk in a Chinese population [16]. In contrast, it has been reported that the CYP2A6 deficient allele was a factor associated with reduced lung cancer susceptibility in Japanese, Bangladeshi, and African American cohorts [10e12, 28,29]. On the other hand, no association between CYP2A6 genotypes and lung cancer risk was found in several other studies [15,17,30,31].…”

CYP2A6 Genotyping Methods and Strategies Using Real-Time and End Point PCR Platforms

“…The choice of CYP2A6 alleles to genotype depends largely on the allele frequencies within the population under study [4,16,17,26]. For statistical analyses individuals are often separated by genotype into predicted reduced or normal CYP2A6 metabolic activity groups [5,6] with the caveat that activity predictions may be substrate specific. Gene variants affecting the amount of CYP2A6 protein (e.g.…”

“…risk factor for lung cancer among Caucasian, African American and Japanese smokers [5][6][7][8], and CYP2A6 enzymatic activity, which is influenced by genetic polymorphisms, has been investigated as a tool for optimizing the selection of smoking cessation pharmacotherapy [9][10][11].…”

Polymorphic Variants of Cytochrome P450

“…Recently, several additional CYP2A6 alleles that are more common among African-Americans have been detected and characterized (Mwenifumbo, Zhou, Benowitz, Sellers, & Tyndale, 2010). In studies on lung cancer susceptibility involving two independent African-American populations, CYP2A6-decreased activity alleles were associated with a significantly decreased risk of lung cancer though, slightly unexpectedly, subgroup analysis suggested the decreased risk related only to males in both community groups with no effect for females (Wassenaar et al, 2015). The numbers of female cases were lower than males but this seems unlikely to explain the relatively large difference seen between the genders.…”