Catechol‐O‐methyltransferase (COMT) gene variants: Possible association of the Val158Met variant with opiate addiction in hispanic women

Abstract

Catechol-O-methyltransferase (COMT) catalyzes the breakdown of catechol neurotransmitters, including dopamine, which plays a prominent role in drug reward. A common single nucleotide polymorphism (SNP), G472A, codes for a Val158Met substitution and results in a fourfold down regulation of enzyme activity. We sequenced exon IV of COMT gene in search for novel polymorphisms and then genotyped four out of five identified by direct sequencing, using TaqMan assay on 266 opioid-dependent and 173 control subjects. Genotype frequencies of the G472A SNP varied significantly (P = 0.029) among the three main ethnic/cultural groups (Caucasians, Hispanics, and African Americans). Using a genotype test, we found a trend to point-wise association (P = 0.053) of the G472A SNP in Hispanic subjects with opiate addiction. Further analysis of G472A genotypes in Hispanic subjects with data stratified by gender identified a pointwise significant (P = 0.049) association of G/A and A/A genotypes with opiate addiction in women, but not men. These point-wise significant results are not significant experiment-wise (at P <0.05) after correction for multiple testing. No significant association was found with haplotypes of the three most common SNPs. Linkage disequilibrium patterns were similar for the three ethnic/ cultural groups. Männistö and Kaakkola, 1999]. There are two forms of COMT in humans and other mammals. The soluble form (S-COMT) is 50 amino acids shorter than the membrane-bound form (MB-COMT). The variant forms are generated through alternative splicing. In most tissues, S-COMT accounts for only a small fraction of overall COMT activity [Rivett et al., 1983]. The highest ratios of MB-COMT to S-COMT are in the brain, and since MB-COMT has a higher substrate affinity for catecholamines than the soluble form, this MB-COMT may be important in regions where substrate levels are low [Rivett and Roth, 1982;Rivett et al., 1983;Roth, 1992;Männistö and Kaakkola, 1999]. KeywordsThe human COMT gene is located on chromosome 22q11.21, and MB-COMT is organized into six exons [Grossman et al., 1992;Tenhunen et al., 1994]. A common missense polymorphism (G472A, Val158Met substitution in the membrane-bound form) in exon IV of the COMT gene is well recognized to account for heritable differences in enzyme thermolability and activity [Weinshilboum and Dunnette, 1981;Lotta et al., 1995;Lachman et al., 1996]. The Met variant of the enzyme has activity fourfold lower compared to the Val variant. Variants of the COMT gene have been associated in some, but not all, studies with schizophrenia [e.g., Matthysse and Baldessarini, 1972;Egan et al., 2001], panic disorder [e.g., Hamilton et al., 2002;Woo et al., 2004], major depression and bipolar disorders [e.g., Fahndrich et al., 1982;Massat et al., 2005], obsessive compulsive disorder [e.g., Karayiorgou et al., 1997Karayiorgou et al., , 1999Niehaus et al., 2001], attention deficit hyperactivity disorder [e.g., Eisenberg et al., 1999], and efficacy of response to L-Dopa in the treatment of Parkins...

Pharmacotherapy in the Treatment of Addiction: Methadone

“…The only one of our specific hypothesis-driven studies of the human molecular genetics that has yielded gender differences is in the catechol- O -methyl transferase gene ( COMT )23. In this study, we found that a very common and functional variant of the COMT gene is significantly associated with heroin addiction, but only in Hispanic subjects23.…”

Functional Interactions between Endogenous Cannabinoid and Opioid Systems: Focus on Alcohol, Genetics and Drug-Addicted Behaviors

“…In the following section, we will describe the main findings that address the relationships between specific polymorphisms in both the endogenous systems and drug addiction. First, when we grouped all of the results, we noticed that most studies could be clustered as follows: some studies compared different populations such as African-Americans, Caucasians, Hispanics, Chinese, and Indians, [226][227][228], as well as gender differences [229]. Others explored how certain haplotypes correlate with other mutations [227,230] or studied associations between addiction phenotypes (e.g., to opiates or to alcohol) [231,232] or associations with psychiatric traits such psychosis induced by a substance [233].…”

HIV serostatus differs by catechol-O-methyltransferase Val158Met genotype

“…The COMT Val158Met polymorphism (rs4680) accounts for significant variability in COMT function whereby the rare (Met) allele is associated with decreased COMT function, lower dopamine metabolism, and increased cortical dopamine 2 . The Met allele has been associated with unprotected sex 3 and illicit drug use 4 , risk behaviors that are related to dopamine and are primary risk factors for HIV infection. We, therefore, examined whether or not the distribution of the Val158Met polymorphism differed between HIV-infected and HIV-uninfected women and found that HIV-infected women were significantly more likely to carry the Met allele compared to HIV-uninfected women.…”

“…Furthermore, among male methamphetamine users with executive dysfunction, Met allele carriers (i.e., Val/Met, Met/Met) reported greater risky sexual behaviors compared to men homozygous for the Val/Val genotype 3 . Propensity for addiction has been associated with the low activity Met/Met genotype among Hispanic females 4 and the high activity Val/Val genotype among male-dominant samples Caucasians 8 . The mixed findings may be due to sex-specific relationships between COMT and cognitive/emotional outcomes since estradiol down-regulates COMT 9 and evidence supports a sex difference in the impact of COMT on psychiatric outcomes 10 .…”