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

Abstract

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). 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'-hydroxycotinine were quantified. The contribution of UGT2B10 genetic score to cotinine concentration was determined. 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'-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. UGT2B10 genotype is a major contributor to cotinine levels and explains the majority of high serum cotinine in African American smokers. 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.