UGT2B10 Genotype Influences Serum Cotinine Levels and Is a Primary Determinant of Higher Cotinine in African American Smokers

Abstract

Background: Cotinine is the most widely used biomarker of tobacco exposure. At similar smoking levels, African Americans have higher serum cotinine than Whites. UGT2B10-catalyzed cotinine glucuronidation impacts these levels, and African Americans often have low UGT2B10 activity due to a high prevalence of a UGT2B10 splice variant (rs2942857).Methods: Two UGT2B10 SNPs (rs6175900 and rs2942857) were genotyped in 289 African Americans and 627 White smokers. Each smoker was assigned a genetic score of 0, 1, or 2 based on the number of variant alleles. Total nicotine equivalents (TNE), the sum of nicotine and six metabolites, and serum cotinine and 3 0 -hydroxycotinine were quantified. The contribution of UGT2B10 genetic score to cotinine concentration was determined.Results: Serum cotinine was significantly higher in smokers with UGT2B10 genetic scores of 2 versus 0 (327 ng/mL vs. 221 ng/mL; P < 0.001); TNEs were not different. In a linear regression model adjusted for age, gender, cigarettes per day, TNE, race, and CYP2A6 activity, geometric mean cotinine increased 43% between genetic score 2 versus 0 (P < 0.001). A 0.1 increase in the CYP2A6 activity ratio, 3 0 -hydroxycotinine/cotinine, resulted in a 6% decrease in cotinine. After adjustment for UGT2B10 genotype and the other covariants, there was no significant difference in serum cotinine by race.Conclusions: UGT2B10 genotype is a major contributor to cotinine levels and explains the majority of high serum cotinine in African American smokers.Impact: Cotinine levels in smokers may greatly overestimate tobacco exposure and potentially misinform our understanding of ethnic/racial difference in tobacco-related disease if UGT2B10 genotype is not taken into account.

Biochemistry of nicotine metabolism and its relevance to lung cancer

“…One recent finding of note is the recognition that a UGT2B10 splice variant is a significant contributor to the higher plasma cotinine levels found in smokers of African compared to European ancestry (100,101). This difference in cotinine was first reported more than 30 years ago, and it is, in part, due to more intense smoking (98).…”

“…Smokers who are heterozygous for either the UGT2B10 splice variant or the Asp67Tryr variant have on average 19% higher plasma cotinine concentrations. These differences are observed after adjustment for smoking dose (cigarettes per day and total nicotine equivalents) and P450 2A6 activity (101).…”

“…With the exception of smokers who carry two CYP2A6 deleted alleles, UGT2B10 variants and cotinine glucuronidation levels influence blood cotinine concentrations significantly more than does P450 2A6 activity (100,101). At similar levels of smoking, individuals who are homozygous for the CYP2A6*4 deletion allele have significantly lower plasma cotinine levels than do individuals who carry CYP2A6 alleles coding for fully functional enzymes (51,63).…”

“…Plasma cotinine concentrations are on average 50% higher in African Americans than in Whites at the same levels of smoking, and much of this difference can be explained by the prevalence of UGT2B10 splice variant in African Americans (101). Recognizing the contribution of UGT2B10 genotype to serum (or saliva) cotinine levels is critical to understanding the relationship of an individual's cotinine level to smoking exposures and ultimately the relationship to lung cancer risk.…”

“…UGT2B10 genotype also has a significant impact on urinary cotinine levels. UGT2B10 deficient smokers have significantly higher levels of urinary cotinine, while total cotinine levels, the sum of cotinine and cotinine glucuronide, are lower compared to smokers with "normal" UGT2B10 activity (50,100,101). Despite some limitations of cotinine as a biomarker of tobacco exposure, several studies have established plasma cotinine and urinary total cotinine levels as predictors of lung cancer risk after adjustment for cigarettes per day (106)(107)(108)(109)(110)(111)(112).…”