Significant Association of Catechol-O-Methyltransferase (COMT) Haplotypes with Nicotine Dependence in Male and Female Smokers of Two Ethnic Populations

Abstract

The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three-to fourfold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z ¼ À3.35; P ¼ 0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z ¼ À2.92; P ¼ 0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z ¼ 3.16; P ¼ 0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.

Gender-Dependent Association of the Functional Catechol-O-Methyltransferase Val158Met Genotype with Sensation Seeking Personality Trait

“…This finding is in line with our data, where Val allele is connected with the impulsivity-related behavior sensation seeking, which is a main characteristic of ADHD behavioral pattern (Qian et al, 2003). Of note, gender-by-COMTgenotype effects have also been observed for the performance in cognitive test (O'Hara et al, 2006) and for nicotine dependence (Beuten et al, 2006). Apart from the behavioral level, some evidence indicates that the COMT genotype also affects cerebral structure (Kates et al, 2006) or function (Rybakowski et al, 2002) in a gender specific way.…”

Sex Modulates the Associations Between the COMT Gene and Personality Traits

“…This finding adds to the growing literature on sex-COMT interaction effects on phenotypes ranging from psychiatric disorders (Harrison and Tunbridge, 2008) to personality traits such as sensation seeking (Lang et al, 2007) and behavioral inhibition system (Reuter et al, 2006b). Beyond the COMT gene and personality, of course, there is a growing literature of sex-dependent genetic effects on behavior, including performance on cognitive tests (O 'Hara et al, 2006), nicotine dependence (Beuten et al, 2006), adolescent delinquency and thrill seeking (Dmitrieva et al, 2011), and ADHD (Qian et al, 2003).…”

The lack of association between angiotensin‐converting enzyme gene insertion/deletion polymorphism and nicotine dependence in multiple sclerosis

“…In line with gender‐specific differences in the effect of the ACE‐I/D polymorphism in various conditions and/or diseases, such as blood pressure (among healthy individuals) (Avila‐Vanzzini et al., 2015), hypertension (Higaki et al., 2000; Sipahi, Budak, Şen, Ay1, & Şener, 2006), schizophrenia (Mazaheri, 2015; Nadalin, Buretić‐Tomljanović, Ristić, Jonovska, & Tomljanović, 2015; Nadalin et al., 2012), as well as MS (Lovrečić et al., 2006), and according to observations of gender–gene interaction in risk for nicotine dependence in general population (Beuten, Payne, Ma, & Li, 2006; Beuten et al., 2005; Nedic et al., 2010; Tochigi et al., 2007) and specific diseases (i.e., schizophrenia) (Nadalin, Buretić‐Tomljanović, Rebić, Pleša, & Šendula Jengić, 2016) association analyses between ACE‐I/D polymorphism and smoking habits were performed separately among male and female patients. Furthermore, there is also evidence that estrogen may influence dopaminergic neurotransmission, since it has been observed that estrogen treatment reduces dopamine receptor D2 levels in several rat brain regions (Chavez et al., 2010).…”