Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health

Objectives: Catechol-O-methyltransferase plays a central role in the metabolism of biogenic amines such as norepinephrine, dopamine and serotonin. Functional studies have demonstrated a dose relationship between Val158Met genotypes and catechol-O-methyltransferase activity. Compared with the Val158Val genotype, the Val158Met and Met158Met genotypes result in two- and four-fold reductions in catechol-O-methyltransferase activity, respectively. Two recent reports have observed the association between the Met158Met genotype and risk of anxiety in adult populations. We examined the association between the Val158Met genotypes and propensity to anxiety across adolescence.

Methods: Participants were drawn from an eight-wave study of the mental and behavioural health of over 2000 young Australians followed from 14 to 24 years of age (Victorian Adolescent Health Cohort Study, 1992 to present). DNA was received from 962 participants using a cheek swab collection method.

Results: The odds of reporting persistent episodic anxiety (phobic avoidance, panic attacks) were doubled among carriers of the Met158Met genotype (odds ratio 2.0, 95% confidence interval 1.1-3.4, P=0.014). A dose relationship between additional copies of the Met158 allele and persistent episodic anxiety was also observed (1.5, 1.1-1.94, P=0.007). Stratification by sex showed that the risk effect of the Met158 allele was among females only. No association was observed for measures of neuroticism, persistent generalized anxiety, or a composite measure of psychiatric distress.

Conclusion: These data replicate previous findings suggesting association between the Val158Met polymorphism and specific expressions of anxiety among females.

Associations of the SREBP-1c gene polymorphism with gender-specific changes in serum lipids induced by a high-carbohydrate diet in healthy Chinese youth

We investigated the possible association between the sterol regulatory element-binding protein-1c gene (SREBP-1c) rs2297508 polymorphism and the changes in lipid profiles in a high-carbohydrate and low-fat (high-CHO/LF) diet in a Chinese population well characterized by a lower incidence of coronary heart disease and a diet featuring higher carbohydrate and lower fat. Fifty-six healthy youth (aged 22.89 ± 1.80 years) were given wash-out diets of 31% fat and 54% carbohydrate for 7 days, followed by the high-CHO/LF diet of 15% fat and 70% carbohydrate for 6 days, without total energy restriction. Fasting blood samples were collected. Serum variables of lipid and glucose metabolism after the wash-out and high-CHO/LF diets, as well as the rs2297508 polymorphism, were analyzed. Compared with the male subjects on the wash-out diet, significantly elevated levels of high-density lipoprotein cholesterol (HDL-C) and decreased levels of apolipoprotein B-100 were observed in the male carriers of the C allele after the high-CHO/LF diet. In the female subjects, significantly increased triacylglycerol levels, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were found in the GG genotype after the high-CHO/LF diet. These results suggest that the C allele of the rs2297508 polymorphism is associated with a retardation of the increases in serum triacylglycerol, serum insulin, and HOMA-IR in females and with the elevated serum HDL-C in males after the high-CHO/LF diet.

Nicotine dependence in a prospective population-based study of adolescents : the protective role of a functional tyrosine hydroxylase polymorphism

Dopamine is a key neurotransmitter of the mesolimbic reward pathway in the human brain, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. Consequently, the gene encoding TH is a strong candidate for involvement in the genetic component of addiction. The importance of this gene in nicotine dependence is supported by many studies showing a link between nicotine administration and TH expression. A functional tetranucleotide repeat polymorphism within intron 1 of the TH gene (HUMTH01-VNTR) has been shown to modify tobacco use in two independent Caucasian samples from the USA and Australia. Using information drawn from an eight-wave Australian population-based longitudinal study of adolescent health, we tested the effect of the HUMTH01-VNTR on nicotine dependence. Comparisons were made between dependent smokers and non-dependent smokers. These data provide further support for a protective association between the K4 allele and dependent smoking (odds ratio 0.54, 95% confidence interval 0.28-1.0). No associations were observed at any of three other common TH polymorphisms (rs6356, rs6357 and HUMTH01-PstI). Including these data, three independent studies, two of which use identical phenotypes, have now identified a protective relationship between the K4 allele of the functional HUMTH01-VNTR polymorphism and high-level smoking.

Association between dependent smoking and a polymorphism in the tyrosine hydroxylase gene in a prospective population-based study of adolescent health

This study reports pilot data on an association between tobacco dependence and a five-allele tetranucleotide repeat polymorphism in the first intron of the tyrosine hydroxylase (TH) gene. One hundred and twenty-six Australian adolescents who had participated in the Health in Transition Study (1993–1997), and who showed patterns of either dependent or nondependent smoking across four waves of data collection, consented to participation in the pilot study. The smoking status of those recruited was confirmed using a telephone-administered drug use questionnaire during 2000. Tobacco dependence was defined as smoking more than 6 days per week and more than 10 cigarettes per day during wave 5 (year 2000) and at lfeast one prior wave (n = 58). A second, more stringent phenotype included smoking within an hour of waking (n = 37). The control group comprised adolescents who had used tobacco but had remained low-level social smokers across each wave of data (n = 56). DNA was collected using a mouthwash procedure. Using the more strictly defined tobacco dependence phenotype, and after adjusting for sex, a significant protective association was found between the K4 allele and tobacco dependence (OR 0.27, 95% confidence interval [CI] 0.09, 0.82). No association was found using the liberal criteria of tobacco dependence (OR 0.51, 95% confidence interval [CI] 0.23, 1.2). These preliminary results replicate a previous association between tobacco use and the K4 allele of the TH gene (Lerman et al., 1997). The potential significance of including time to first cigarette in definitions of tobacco dependence and the possible role that these TH variants might play in tobacco dependence are discussed.

Dopamine transporter (DAT1) VNTR polymorphism and alcoholism in two culturally different populations of South India

It is well established that the central dopaminergic reward pathway is likely involved in alcohol intake and the progression of alcohol dependence. Dopamine transporter (DAT1) mediates the active re-uptake of DA from the synapse and is a principal regulator of dopaminergic neurotransmission. The gene for the human DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 16 copies in the 3′-untranslated region (UTR) of the gene. To assess the role of this gene in alcoholism, we genotyped the VNTR of DAT1 gene in a sample of 206 subjects from the Kota population (111 alcohol dependence cases and 95 controls) and 142 subjects from Badaga population (81 alcohol dependence cases and 61 controls). Both populations inhabit a similar environmental zone, but have different ethnic histories. Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using PCR and electrophoresis. The association of DAT1 with alcoholism was tested by using the Clump v1.9 program which uses the Monte Carlo method. In both Kota and Badaga populations, the allele A10 was the most frequent allele followed by allele A9. The genotypic distribution is in Hardy–Weinberg equilibrium in both cases and control groups of Kota and Badaga populations. The DAT1 VNTR was significantly associated with alcoholism in Badaga population but not in Kota population. Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcoholism, but that these associations are population specific.

Identification of a novel polymorphism in the 3'UTR of the L-arginine transporter gene SLC7A1 : contribution to hypertension and endothelial dysfunction

Background— Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension. We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism.

Methods and Results— We have identified a novel C/T polymorphism in the 3′UTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 gene (SLC7A1). The minor T allele significantly attenuates reporter gene expression (P<0.01) and is impaired in its capacity to form DNA-protein complexes (P<0.05). In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects (P<0.001). Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives (P<0.001). To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing l-arginine transporter SLC7A1. The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (−log EC50 for wild-type versus Slc7A1 transgenic: 6.87±0.10 versus 7.56±0.13; P<0.001). This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells.

Conclusions— The present study identifies a key, functionally active polymorphism in the 3′UTR of SLC7A1. As such, this polymorphism may account for the apparent link between altered endothelial function, l-arginine, and nitric oxide metabolism and predisposition to essential hypertension.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal femals

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

Association between mitochondrial DNA 10398A>G polymorphism and the volume of amygdala

Mitochondrial calcium regulation plays a number of important roles in neurons. Mitochondrial DNA (mtDNA) is highly polymorphic, and its interindividual variation is associated with various neuropsychiatric diseases and mental functions. An mtDNA polymorphism, 10398A>G, was reported to affect mitochondrial calcium regulation. Volume of hippocampus and amygdala is reportedly associated with various mental disorders and mental functions and is regarded as an endophenotype of mental disorders. The present study investigated the relationship between the mtDNA 10398A>G polymorphism and the volume of hippocampus and amygdala in 118 right-handed healthy subjects. The brain morphometry using magnetic resonance images employed both manual tracing volumetry in the native space and voxel-based morphometry (VBM) in the spatially normalized space. Amygdala volume was found to be significantly larger in healthy subjects with 10398A than in those with 10398G by manual tracing, which was confirmed by the VBM. Brain volumes in the other gray matter regions and all white matter regions showed no significant differences associated with the polymorphism. These provocative findings might provide a clue to the complex relationship between mtDNA, brain structure and mental disorders.

Escitalopram efficacy in depression a cross-ethnicity examination of the serotonin transporter promoter polymorphism

Current evidence suggests that polymorphism in the serotonin transporter gene (5-HTTLPR) predicts antidepressant efficacy in whites but less so in Asians. However, it is not clear whether this effect can be observed for specific types of antidepressant drugs. White (n = 47) and Korean (n = 118) participants with major depressive disorder were treated with escitalopram and assessed over 8 weeks. Among those with the l/l but not l/s or s/s genotypes, whites had greater depression score reductions, response rates, and remission rates compared with Koreans. Our results suggest that 5-HTTLPR predicts escitalopram efficacy in an ethnicity-dependent manner.