Gene-centric analysis of serum cotinine levels in African and European American populations

Abstract

To date, most genetic association studies of tobacco use have been conducted in European American subjects using the phenotype of smoking quantity (cigarettes per day). However, smoking quantity is a very imprecise measure of exposure to tobacco smoke constituents. Analyses of alternate phenotypes and populations may improve our understanding of tobacco addiction genetics. Cotinine is the major metabolite of nicotine, and measuring serum cotinine levels in smokers provides a more objective measure of nicotine dose than smoking quantity. Previous genetic association studies of serum cotinine have focused on individual genes. We conducted a genetic association study of the biomarker in African American (N=365) and European American (N=315) subjects from the Coronary Artery Risk Development in Young Adults study using a chip containing densely-spaced tag SNPs in ∼2100 genes. We found that rs11187065, located in the non-coding region (intron 1) of insulin-degrading enzyme (IDE), was the most strongly associated SNP (p=8.91 × 10(-6)) in the African American cohort, whereas rs11763963, located on chromosome 7 outside of a gene transcript, was the most strongly associated SNP in European Americans (p=1.53 × 10(-6)). We then evaluated how the top variant association in each population performed in the other group. We found that the association of rs11187065 in IDE was also associated with the phenotype in European Americans (p=0.044). Our top SNP association in European Americans, rs11763963 was non-polymorphic in our African American sample. It has been previously shown that psychostimulant self-administration is reduced in animals with lower insulin because of interference with dopamine transmission in the brain reward centers. Our finding provides a platform for further investigation of this, or additional mechanisms, involving the relationship between insulin and self-administered nicotine dose.

Figure 1

Association between insulin-degrading enzyme (IDE) variants and serum cotinine in Coronary Artery Risk Development in Young Adults (CARDIA) African American cohort. The most significant association in CARDIA African American cohort was with SNP rs11187065 (here in purple) of the gene encoding IDE. The same variant was also associated with serum cotinine levels in CARDIA European Americans (p=0.044).

Figure 2

Association between rs11763963 and serum cotinine in Coronary Artery Risk Development in Young Adults (CARDIA) European American cohort. The most significant association in CARDIA European Americans was with SNP rs11763963 (here in purple), located on chromosome 7 outside of a gene transcript. This SNP is non-polymorphic in African Americans.

Figure 3

Association between mortality factor 4 like 1 (MORF4L1) variants and serum cotinine in Coronary Artery Risk Development in Young Adults (CARDIA) European Americans. The second association in European Americans was on chromosome 15 in MORF4L1. This association was not found in the CARDIA African American cohort (p=0.17).