Variation in CYP2A6 and nicotine metabolism among two American Indian tribal groups differing in smoking patterns and risk for tobacco-related cancer

Abstract

Objectives The Northern Plains (NP) and Southwest (SW) American Indian populations differ in their smoking patterns and lung cancer incidence. We aimed to compare CYP2A6 genetic variation and CYP2A6 enzyme activity (representative of the rate of nicotine metabolism) between the two tribal populations, as these have previously been associated with differences in smoking, quitting, and lung cancer risk. Methods American Indians (N=636) were recruited from two different tribal populations (NP in South Dakota, SW in Arizona) as part of a study conducted as part of the Collaborative to Improve Native Cancer Outcomes P50 project. A questionnaire assessed smoking-related traits and demographics. Participants were genotyped for CYP2A6 genetic variants *1B, *2, *4, *7, *9, *12, *17, and *35. Plasma and/or saliva samples were used to measure nicotine’s metabolites cotinine and 3′-hydroxycotinine and determine CYP2A6 activity (3′-hydroxcotinine/cotinine, i.e. the nicotine metabolite ratio, NMR). Results The overall frequency of genetically reduced nicotine metabolizers, those with CYP2A6 decrease- or loss-of-function alleles, was lower in the NP compared to the SW (P=0.0006). CYP2A6 genotype was associated with NMR in both tribal groups (NP P<0.001, SW P=0.04). Notably, the rate of nicotine metabolism was higher in NP compared to SW smokers (P=0.03), and in comparison to other ethnic groups in the United States. Of the variables studied, CYP2A6 genotype was the only variable to significantly independently influence NMR among smokers in both tribal populations (NP P<0.001, SW P=0.05). Conclusions Unique CYP2A6 allelic patterns and rates of nicotine metabolism among these American Indian populations suggest different risks for smoking and tobacco-related disease.

Variation in CYP2A6 Activity and Personalized Medicine

“…Two American Indian populations, the Northern Plains tribal population of South Dakota and the Southwest tribal population of Arizona, have CYP2A6 allele frequencies that are distinct from White populations, and which also differ significantly between these two tribal groups [ 42 ]. Compared to White individuals, both American Indian populations have a higher frequency of the increase-of-function CYP2A6*1B variant and the reduce-of-function CYP2A6*9 variant.…”

“… a Functional impact toward nicotine metabolism (nicotine C-oxidation); b This table has been adapted from Tanner et al, 2015 [ 41 ], with additional data from Loukola et al, 2015 [ 3 ], Tanner et al, 2017 [ 42 ], the 1000 Genomes dataset [ 43 ], and unpublished work. Additional references for specific variants are provided in the text.…”

P450 Pharmacogenetics in Indigenous North American Populations

“…Tanner et al compared variation in CYP2A6 and NMR in two different AI populations and assessed differences in relation to smoking behaviors and risks [ 25 ]. In Northern Plains (NP) AIs, the CYP2A6*2 , *4 , *9 and *12, the MAFs were 0.3%, 1.6%, 11.9% and 0.3%, respectively, while in AIs from the Southwest (SW) in Arizona the frequencies were 0.6, 0.3, 20.9 and 0.3%, respectively ( Table 4 ) [ 25 ]. CYP2A6*7 and *17 were absent from the Yup’ik, NP and SW populations.…”

“…While CYP2A6*35 was not found in the Yup’ik or NP, it had a MAF of 0.3% in the SW AI population ( Table 4 ). The NP AI population had a lower frequency of CYP2A6 decreased function alleles and a higher rate of nicotine metabolism, compared to SW smokers [ 25 ]. CYP2A6 genetic variants are important to consider clinically because there are negative outcomes associated with higher rates of nicotine metabolism, including increased tobacco consumption, more difficulty with smoking cessation, poorer success with nicotine replacement therapy and elevated risk of lung cancer [ 27 , 75 , 79 ].…”

“…Not only do Indigenous groups often have different allele frequencies compared to other global populations but marked differences in allele frequencies can also be found between subcultures within a given geographical region. Notable findings from the original studies highlighted in this review include the lower frequency of CYP2A6 loss-of-function alleles and a higher rate of nicotine metabolism in the NP AI, compared to a population of SW AI smokers [ 25 ]. With regards to CYP2C9 , there was a lack of CYP2C9*2 in the Canadian Inuit population as well as many Amerindian groups including the Mexicanera, Huichol, Guarijío, Cora, Tarahumara and Purepecha [ 28 , 30 , 31 ].…”