MR and GR functional SNPs may modulate tobacco smoking susceptibility

Abstract

A number of studies have demonstrated that stress is involved in all aspects of smoking behavior, including initiation, maintenance and relapse. The mineralocorticoid (MR) and glucocorticoid (GR) receptors are expressed in several brain areas and play a key role in negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis. As nicotine increases the activation of the HPA axis, we wondered if functional SNPs (single nucleotide polymorphisms) in MR and GR coding genes (NR3C2 rs5522 and NR3C1 rs6198, respectively) may be involved in smoking susceptibility. The sample included 627 volunteers, of which 514 were never-smokers and 113 lifetime smokers. We report an interaction effect between rs5522 and rs6198 SNPs. The odds ratio (OR) for the presence of the NR3C2 rs5522 Val allele in NR3C1 rs6198 G carriers was 0.18 (P = 0.007), while in rs6198 G noncarriers the OR was 1.83 (P = 0.027). We also found main effects of the NR3C1 rs6198 G allele on number of cigarettes smoked per day (P = 0.027) and in total score of the Fagerström Test for Nicotine Dependence (P = 0.007). These findings are consistent with a possible link between NR3C2 and NR3C1 polymorphisms and smoking behavior and provide a first partial replication for a nominally significant GWAS finding between NR3C2 and tobacco smoking.

Corticosteroid receptor genes and childhood neglect influence susceptibility to crack/cocaine addiction and response to detoxification treatment

“…This study also provides evidence that an interaction between genes related to the HPA axis influences the severity of crack/cocaine withdrawal symptoms, which is in agreement with previous results in tobacco smoking (Rovaris et al, 2013b).…”

“…Although a women-only sample has the advantage of homogeneity, extrapolations to the male gender should be made with caution due to gender differences in HPA axis activity (Fernandez-Guasti et al, 2012;Heim et al, 2009;Reynolds et al, 2013;ter Heegde et al, 2015). However, in our previous study with a tobacco smoking sample, significant heterogeneity in odds ratios was not found when SNPgender interactions were considered in Cochran-Mantel-Haenszel analyses (Rovaris et al, 2013b). Due to the prospective cohort design, the stringent inclusion and exclusion criteria and the specificity of our target population, our sample size was relatively small in comparison to other gene-environment mental disorderrelated studies.…”

“…We have chosen NR3C2 rs5522 and NR3C1 rs6198 SNPs as the primary hypothesis of association since they were linked to smoking and presented evidence for interaction in our previous study (Rovaris et al, 2013b). However, we also evaluated in additional analyses two other NR3C1 SNPs (rs10052957-TthIIII and rs41423247-BclI).…”

“…We have previously demonstrated an interaction effect between two functional SNPs (single nucleotide polymorphisms) from the mineralocorticoid (MR) and glucocorticoid receptor (GR) genes on tobacco smoking susceptibility (Rovaris et al, 2013b). Afterward, others have shown that SNPs located in the genes coding these receptors were also associated with cocaine addiction (Levran et al, 2014).…”

“…The second is to verify the potential role of theses SNPs on the severity of crack/cocaine withdrawal symptoms during detoxification treatment. Since it has been suggested that epistasis plays a role in the missing/phantom heritability of complex phenotypes (Zuk et al, 2012), the third goal of this study is to test if the interaction between NR3C2 rs5522 and NR3C1 rs6198 SNPs, previously associated to tobacco smoking susceptibility (Rovaris et al, 2013b), also affects the severity of crack/cocaine addiction.…”