Genetic polymorphism of CYP2D6 and lung cancer risk in African- Americans and Caucasians in Los Angeles County

Abstract

The well described genetic polymorphism of the CYP2D6 gene influences response to a wide variety of therapeutic agents metabolized by the CYP2D6 enzyme product. CYP2D6 also appears to play a role, along with other cytochrome P450 enzymes, in the metabolic activation of the tobacco specific nitrosamine, NNK, as well as metabolism of nicotine to cotinine. While impaired activity of CYP2D6 was strongly protective against lung cancer in some studies, primarily based on phenotyping, the literature is conflicting. The molecular basis of CYP2D6 deficiency is now well understood, enabling the use of genotyping to classify individuals. We therefore examined whether lung cancer risk is reduced by the presence of four CYP2D6 alleles associated with impaired activity due to an inactivating mutation--CYP2D6*4, CYP2D6*3, CYP2D6*5 and CYP2D6*16--among 341 incident cases of lung cancer and 710 population controls of Caucasian or African-American ethnicity in Los Angeles County, California. We did not confirm a strong association between the presence of these inactivating alleles and lung cancer risk [odds ratio (OR) = 0.90, 95% confidence interval (CI) 0.60-1.35 for Caucasians], although there was a small decreased risk among the African-Americans (OR = 0.66, 95% CI 0.38-1.14). Among smokers, when the data are stratified according to lifetime smoking history, there is a suggestion of an association limited to Caucasian smokers of <35 pack-years, the median for all smokers in these data (OR = 0.49, 95% CI 0.23-1.04). However, among African-American smokers, who smoke less than Caucasians, the association did not differ between smoking categories. We also examined the possible role of additional copies of the CYP2D6 gene, which lead to enhanced CYP2D6 activity, in increasing lung cancer risk. Among controls the prevalence of having more than two copies of the CYP2D6 gene and no inactivating alleles was 4.3% for Caucasians and 4.9% for African-Americans. Relative to subjects with an inactivating allele, those with an additional copy of the CYP2D6 gene and no inactivating alleles may be at increased risk of lung cancer, particularly for adenocarcinoma (OR = 3.61, 95% CI 1.08-11.7 for African-Americans and OR = 2.20, 95% CI 0.69-6.0 for Caucasians). Our data suggest that the CYP2D6 genetic polymorphism is not the strong risk factor for lung cancer suggested by some studies of phenotype, but may play a minor role.

Psychosis and catatonia in fragile X: Case report and literature review

“…Prevalence rates of the UM phenotype in American Caucasians is reported to be low at 4.3% compared to those in Ethiopians (30%) and in Saudi Arabian (20%) (69)(70)(71). Acknowledged UM allelic variants are CYP2D6*1,*2,*35, and *41 duplicated and multiduplicated, among those, CYP2D6*2 and *41 are the most frequent variants of CYP2D6 gene that cause extremely increased enzyme activity, wherein the lack of drug response/treatment failure is the most common clinical consequences (72).…”

Polymorphisms for microsomal epoxide hydrolase and genetic susceptibility to COPD

“…This pattern is similar to that observed in previous studies examining polymorphic genotypes and lung cancer risk. The glutathione S transferase M1 (GSTM1) (0/0) (28,29), the CYP1A1 exon 7 and Mspl polymorphisms (29,30), and CYP2D6 polymorphisms (31) have all been shown to be associated with increased risk for lung cancer in light but not heavy smokers. Therefore, genetic variations in the ability to metabolize tobacco smoke toxins are most important in determining risk for lung disease at low levels of exposure, and may be less relevant at higher smoking doses where high levels of tobacco toxin exposure overwhelm polymorphism-induced differences in enzyme activity and/or expression.…”

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

“…However, it has been estimated that the proportion of ethnic minorities in the U.S. population will increase to around 40% by 2020 [18], with the greatest increase seen among Hispanics [19]. The challenge is that individuals of European, African, and Hispanic ancestry have all emigrated from different regions that have different [20] to 29% in Ethiopians [21], and data on what proportion of African-Americans is of Ethiopian descent are lacking. Wide ranges in the prevalence of both the UM and PM phenotypes have also been reported in individuals of European descent (0.8%-10% and 1.5%-10%, respectively) [22][23][24][25].…”

“…The highest frequencies of the UM phenotype are reported in Ethiopians (29%) [21] and Saudi Arabians (21%) [51]. The prevalence rates of the UM phenotype in American Caucasians and Blacks are reported to be 4.3% and 4.9%, respectively [20].…”