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 ¼ 365) and European American (N ¼ 315) subjects from the Coronary Artery Risk Development in Young Adults study using a chip containing densely-spaced tag SNPs in B2100 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 ¼ 8.91 Â 10 À6 ) 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 ¼ 1.53 Â 10 À6 ). 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 ¼ 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.

Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone

“…www.nature.com/scientificreports www.nature.com/scientificreports/ Marginally higher (i.e., trend significance) addiction severity in OUD comorbidity with MetS would support this sort of an interaction regardless of the primary index event. Of note, insulin mediates the homeostatic and reward systems' cross-talk (impairment of which might underlie the chronically relapsing nature of addictive disorders) and it has been successfully tried in nicotine 116,117 and cocaine 118 addiction. It would be of interest to test whether insulin is also able to improve metabolic and reward dysfunction in patients with OUD.…”

Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures

“…Finally, we assessed statistical power to detect a priori genetic loci of interest from an example of a large-scale (1000 s) candidate gene association scan, and an example from a locus nominated by genome-wide association scans (GWAS), with genome-wide significance (GWS) as the statistical threshold. For self-identified non-Hispanic Black current smokers, we selected rs11187065 as an example, identified in the insulin-degrading enzyme gene as the gene-centric SNP most significantly associated with serum cotinine in the Coronary Artery Risk Development in Young Adults (CARDIA) study by Hamidovic et al [ 36 ]. The influence of rs11187065 on serum cotinine was substantial with a β of −85.1 ng/ml, with mean (SE) of 236.5 (8.1) ng/ml from 365 African American smokers [ 36 ].…”

“…For self-identified non-Hispanic Black current smokers, we selected rs11187065 as an example, identified in the insulin-degrading enzyme gene as the gene-centric SNP most significantly associated with serum cotinine in the Coronary Artery Risk Development in Young Adults (CARDIA) study by Hamidovic et al [ 36 ]. The influence of rs11187065 on serum cotinine was substantial with a β of −85.1 ng/ml, with mean (SE) of 236.5 (8.1) ng/ml from 365 African American smokers [ 36 ]. Mean (SD) CPD in the CARDIA sample was 10.5 (7.4), similar to that of the TES (Table 4 ).…”

Genetic variation within the Chrna7 gene modulates nicotine reward‐like phenotypes in mice

“…Insulin‐degrading enzyme mRNA was significantly decreased in α7 KO mice, and previous rodent studies have demonstrated that functional disruption of this gene, results in hyperinsulinemia and glucose intolerance (Fakhrai‐Rad et al ; Farris et al ). Additionally, Ide mRNA expression is altered in rats following nicotine treatment (Polesskaya et al ), whereas an allele of the Ide gene is associated with plasma cotinine levels in both European and African American smokers (Hamidovic et al ). Together with the present study, these data implicate a possible role of Ide in nicotine addiction.…”