Genetic and Environmental Influences on the Ratio of 3’Hydroxycotinine to Cotinine in Plasma and Urine


Swan, G. E., Lessov-Schlaggar, C. N., Bergen, A. W., He, Y., Tyndale, R. F., & Benowitz, N. L. (2009). Genetic and environmental influences on the ratio of 3’hydroxycotinine to cotinine in plasma and urine. Pharmacogenetics and genomics, 19(5), 388.



The ratio of trans-3′hydroxycotinine/cotinine (3HC/COT) is a marker of CYP2A6 activity, an important determinant of nicotine metabolism. This analysis sought to conduct a combined genetic epidemiologic and pharmacogenetic investigation of the 3HC/COT ratio in plasma and urine.


One hundred and thirty-nine twin pairs [110 monozygotic and 29 dizygotic] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine, and metabolites. DNA was genotyped to confirm zygosity and for variation in the gene for the primary nicotine metabolic enzyme, CYP2A6 (variants genotyped: *1B, *1×2, *2, *4, *9, *12). Univariate biometric analyses quantified genetic and environmental influences on each measure in the presence and absence of covariates, including measured CYP2A6 genotype.


There was a substantial amount of variation in the free 3HC/COT ratio in plasma (6 h postinfusion) attributable to additive genetic influences (67.4%, 95% confidence interval=55.9–76.2%). The heritability estimate was reduced to 61.0 and 49.4%, respectively, after taking into account the effect of covariates and CYP2A6 genotype. In urine (collected over 8 h), the estimated amount of variation in the 3HC/COT ratio attributable to additive genetic influences was smaller (47.2%, 95% confidence interval=0–67.2%) and decreased to 44.6 and 42.0% after accounting for covariates and genotype.


Additive genetic factors are prominent in determining variation in plasma 3HC/COT but less so in determining variation in urine 3HC/COT.

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