SIMILARITY OF BLOOD PRESSURE FOR EACH GENOTYPE OF THE INSERTION/DELETION POLYMORPHISM OF THE DIPEPTIDYL CARBOXYPEPTIDASE-1 GENE IN DIFFERENT AGE GROUPS OF PATIENTS WITH SEVERE, FAMILIAL ESSENTIAL HYPERTENSION

1. The association of alleles of an insertion/deletion polymorphism (I/D) of the dipeptidyl carboxypeptidase-1 gene with hypertension is controversial. If a particular allele makes a major contribution to blood pressure, then hypertensives homozygous for this allele could be expected to have higher high blood pressure than those homozygous for the alternate allele. 2. The present study examined this hypothesis by comparing pretreatment blood pressures of hypertensives who had been genotyped for the I/D polymorphism. Blood pressures for different age groups (< 50, 50–59 and ≥60 years) were also examined for each genotype. In addition, several other parameters were examined. 3. Systolic blood pressures were found to be 167 ± 3, 167 ± 3 and 170 ± 6 mmHg (mean ± s.e.) for the genotypes II, ID and DD, respectively. Diastolic blood pressures were 113 ± 4, 111 ± 2 and 111 ± 4, for the respective genotypes. One-way anova showed that the respective blood pressure values did not differ significantly across genotypes. Blood pressures for different age groups of hypertensives were also similar. 4. In addition, body mass index, mean age and sex did not differ between genotypes, either for the group as a whole or for the different age groups. 5. In conclusion, the present study could find no evidence to support a genetic association between the I/D polymorphism of DCP1 and blood pressure in a group with severe, familial hypertension living in Sydney.     

GENOTYPIC INFLUENCE ON PLASMA DIPEPTIDYL CARBOXYPEPTIDASE-1 ACTIVITY IN HYPERTENSIVES

1. Plasma dipeptidyl carboxypeptidase-1 (DCP1; angiotensin I-converting enzyme, kininase II; EC 3.4.15.1) tracks with the deletion allele in genotypes of a 287 bp insertion/deletion (I/D) polymorphism of its gene, DCP1, in healthy Caucasian populations. The aim of the present study was to see whether genotype has a similar influence on plasma DCP1 in hypertensives. 2. The study involved 35 Caucasian patients with severe, familial essential hypertension, who were not being treated with DCP1 inhibitors, and 94 normotensives. Genotyping for the I/D polymorphism was performed by polymerase chain reaction and plasma DCP1 activity was measured by rate of hydrolysis of both [³H]-Hip-Gly-Gly and Hip-His-Leu. 3. Plasma DCP1 activity (nmol Gly-Gly/min per mL; mean ± s.e.m.) was 67 ± 2, 82 ± 4 and 91 ± 6 in II, ID and DD hypertensives, respectively, which was similar to values of 68 ± 4, 82 ± 3 and 94 ± 3 in normotensives (P= 0.0001 by one-way analysis of variance). Results for the His-Leu assay indicated similar tracking with genotype. 4. The Michaelis constant (μmol Hip-Gly-Gly/mL; mean ± s.e.m., n= 10) for DD subjects was the same as for II subjects (10.6 ± 1.6 vs 11.1 ± 2.3; P = 0.86). 5. In conclusion, in severely hypertensive Caucasian subjects, plasma DCP1 activity is subject to a similar genotypic influence in hypertensives as has been reported previously in normotensives. Furthermore, the plasma DCP1 enzyme itself appears to be functionally similar for each genotype.     

FREQUENCIES OF VARIANTS OF CANDIDATE GENES IN DIFFERENT AGE GROUPS OF HYPERTENSIVES

1. In severe, familial hypertension, we have reported that the proportion of patients homozygous for the deletion allele of an insertion/deletion polymorphism of the angiotensin I-converting enzyme gene is markedly decreased in older age groups, suggesting that this genotype is associated with increased risk of premature death. The aim of the present study was to examine the relationship with age, of variants of other genes that encode proteins having an influence on the cardiovascular system. 2. Genotypes of 13 different variants at 12 relevant genetic loci were determined by either Southern blotting, followed by hybridization probing, or polymerase chain reaction techniques, as appropriate, using genomic DNA extracted from blood leukocytes. Genotype numbers were then assigned to the age categories of < 50, 50–59 and ≥60 years. 3. Polymorphisms at the atrial natriuretic factor, antithrombin III, renin, angiotensinogen, neuropeptide-Y Y1 receptor, insulin, α₂-adrenoceptor, β₁-adrenoceptor, growth hormone, low density lipoprotein receptor, insulin receptor and renal kallikrein gene loci were found to display similar allele frequencies in each age group of hypertensives, as well as in normotensive controls. 4. In conclusion, we were unable to detect any difference with age for a range of variants of genes whose products have cardiovascular significance, suggesting that, like most polymorphisms, they carry no selective survival advantage or disadvantage in the hypertensive and normotensive population groups studied.     

Lack of in vivo mutagenicity of 1,2‐dichloropropane and dichloromethane in the livers of gpt delta rats administered singly or in combination

1,2‐Dichloropropane (1,2‐DCP) and dichloromethane (DCM) are possible causative agents associated with the development of cholangiocarcinoma in employees working in printing plant in Osaka, Japan. However, few reports have demonstrated an association between these agents and cholangiocarcinoma in rodent carcinogenicity studies. Moreover, the combined effects of these compounds have not been fully elucidated. In the present study, we evaluated the in vivo mutagenicity of 1,2‐DCP and DCM, alone or combined, in the livers of gpt delta rats. Six‐week‐old male F344 gpt delta rats were treated with 1,2‐DCP, DCM or 1,2‐DCP + DCM by oral administration for 4 weeks at the dose (200 mg kg⁻¹ body weight 1,2‐DCP and 500 mg kg⁻¹ body weight DCM) used in the carcinogenesis study performed by the National Toxicology Program. In vivo mutagenicity was analyzed by gpt mutation/Spi⁻ assays in the livers of rats. In addition, gene and protein expression of CYP2E1 and GSTT1, the major enzymes responsible for the genotoxic effects of 1,2‐DCP and DCM, were analyzed by quantitative polymerase chain reaction and western blotting. Gpt and Spi⁻ mutation frequencies were not increased by 1,2‐DCP and/or DCM in any group. Additionally, there were no significant changes in the gene and protein expression of CYP2E1 and GSTT1 in any group. These results indicated that 1,2‐DCP, DCM and 1,2‐DCP + DCM had no significant impact on mutagenicity in the livers of gpt delta rats under our experimental conditions. Copyright © 2016 John Wiley & Sons, Ltd.     

HYPOTHESIS: AN ANGIOTENSIN CONVERTING ENZYME/GENOTYPE,PRESENT IN ONE IN THREE CAUCASIANS,IS ASSOCIATED WITH AN INCREASED MORTALITY RATE

• 1 This review argues that the deletion (D) allele of an insertion (I)/deletion polymorphism of the angiotensin I-converting enzyme (ACE) gene is a marker for a variant associated with increased ACE expression, as well as myocardial infarction (MI) and other life-threatening conditions.
• 2 By examination of I/D frequency in different age groups of individuals having well-known risk factors, it appears that homozygosity for the D allele may be associated with an increased risk of premature death in subjects at high-risk of cardiovascular events. For the risk factor hypertension, the odds ratio for DD vs II in patients aged ≥60 years was 6.6.
• 3 Besides in MI itself, the DD genotype appears to be also more prevalent in MI patients who develop restenosis several months after balloon angioplasty, patients with various forms of heart failure, those with ventricular hypertrophy and diabetic patients who develop nephropathy.
• 4 Particular genotypes of other components of the renin-angiotensin system may add to the risk conferred by the ACE DD genotype.
• 5 Emerging evidence therefore suggests that the ACE genotype may eventually be placed on the list of common, well-known risk factors for fatal cardiovascular events.

     

Allele and genotype frequencies of polymorphic DCP1, CETP, ADRB2, and HTR2A in the Egyptian population

OBJECTIVE: The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: A sensitive real-time polymerase chain reaction assay was developed and successfully applied for genotyping of the consensus (wild-type) alleles plus five variants of four genes: DCP1 [the insertion allele ( I) versus the deletion allele ( D)], CETP*TaqI ( B1 versus B2), ADRB2*R16G, ADRB2*Q27E, and HTR2A*102T>C. This study was carried out in 242 unrelated Egyptian subjects and is the first to describe these allelic variants in the Egyptian population. RESULTS: The frequencies of the tested alleles were found as: DCP1 ( I: D, 0.32:0.68), CETPTaqI ( B1: B2, 0.65:0.35), ADRB2*R16G ( Arg16: Gly16, 0.57:0.43), ADRB2*Q27E ( Gln27: Glu27, 0.76:0.24), and HTR2A*102T>C ( T102: C102, 0.53:0.47). The common Arabian ancestors of the Egyptians, Spanish, Saudi, and Emirate had created a common pattern of distribution of some allelic variants ( DCP1 and CETP). However, in the genotyping of ADRB2, the frequency of the polymorphism at codon 16 was found to be similar to the Chinese population, whereas that at codon 27 was similar to African-Americans with significant differences than other Caucasian populations. The frequency of the HTR2A*102T>C variant appeared to be similar to many Caucasian populations and African-Americans. CONCLUSIONS: We have explored the frequencies of important allelic variants DCP1, CETP, ADRB2, and HTR2A among the Egyptian population focusing on the ethnic diversity in the distribution of the tested mutant alleles. Our results may help in better understanding the observed ethnic variation in angiotensin-converting enzyme inhibition and atherosclerosis therapy. It also may contribute to better characterization of interethnic differences in isoprenaline and clozapine response, which will have implications for the cost effective and rational prescribing of these drugs.     

Association of ACE genotype and predominantly diastolic hypertension: a preliminary study.

BACKGROUND: The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) polymorphism has been established as a cardiovascular risk factor in some populations, but the association with essential hypertension is controversial. Predominantly diastolic hypertension (PDH), or narrow pulse pressure hypertension, has been shown to have increased peripheral resistance. Because a DD genotype has been associated with higher plasma ACE levels and angiotensin II activity, we genotyped PDH patients for ACE I/D polymorphism. METHODS: Ninety-three patients with systolic blood pressure (BP)<140 mmHg systolic and diastolic BP>90 mmHg, or BP>140/90 mmHg with a pulse pressure<45 mmHg, were defined as PDH. The II, ID and DD genotype variants of ACE were characterised by the triple primer nested-PCR method. Results were compared to 75 normotensive control individuals. Statistical significance was assessed by the Chi square test. RESULTS: The genotype distribution among PDH patients was II=20 (21.5%), ID=34 (36.5%), DD=39 (42%), while the distribution among normotensive controls was II=16 (21.4%), ID=42 (56%), DD=17 (22.6%). The difference in genotype distribution between PDH patients and controls was significant (p<0.02). ACE allele frequencies in PDH patients and controls were D=0.60, I=0.40 and D=0.51, I=0.49, respectively, statistically non-significant (ns). CONCLUSION: These results suggest an association between ACE genotype DD and predominantly diastolic hypertension.     

Distribution of the <Emphasis Type="Italic">GNB3</Emphasis> 825C>T polymorphism among Brazilians: impact of population structure

Objective To describe the impact of population admixture on the distribution of the GNB3 825C>T polymorphism in the heterogeneous Brazilian population. Methods Individual DNA from 236 healthy Brazilians, self-identified as White, Intermediate and Black, was genotyped for a set of insertion/deletion polymorphisms that have been previously validated as ancestry informative markers (AIMs). The GNB3 825C>T polymorphism was detected by PCR-RFLP. Non-linear logistic regression modeling was applied to describe the association between the GNB3 825C>T polymorphisms and the African component of ancestry (ACA) estimated by the AIMs. Results The GNB3 825C>T allele and genotype distribution differed significantly across the three self-reported groups (P < 0.0001, χ² test), with a trend for increasing frequency of both the GNB3 825T allele and the TT genotype from White to Intermediate to Black individuals (P < 0.0001, χ² test for trend in proportions). Non-linear logistic regression showed that the odds of having the GNB3 825C>T allele increase monotonically (P < 0.0001, Wald statistics) with increasing ACA throughout the ACA range (0.136–0.897) observed in the overall population sample, irrespective of “racial/color” self-identification. Conclusion The present data on the GNB3 825C>T polymorphism support the notion that interethnic admixture, which is a source of spurious genotype–phenotype associations in pharmacogenetic/-genomic studies, must be dealt with as a continuous variable, rather than proportioned in arbitrary sub-categories for the convenience of data quantification and analysis.     

Ageing and diabetes: implications for brain function

Polymorphisms of the renin-angiotensin system are associated with cardiovascular disorders, possibly as a consequence of increased brain angiotensin II activity. Within the brain, angiotensin controls blood pressure, fluid balance and hormone secretion; it also influences behaviour: reduction of central angiotensin function has both antidepressant-like and axiolytic-like actions. Evidence concerning the role of the renin-angiotensin system in learning and memory is contradictory, although more studies support the proposal that angiotensin reduces cognitive function. Studies of renin-angiotensin system genotype and psychological status have suggested an association between the angiotensin-converting enzyme deletion allele and age related cognitive decline, but a greater prevalence of the insertion allele in Alzheimer's disease. The deletion allele has also been associated with depressive illness, as has the M allele of the angiotensinogen gene although other studies have failed to replicate these findings. The role of the brain renin-angiotensin system in human psychopathology remains to be fully explored.     

CYP2C9*3 allelic variant is associated with metabolism of irbesartan in Chinese population

Objective There is considerable variability in the individual pharmaceutical dosages required to achieve optimal therapeutic effects, which may be due to environmental or genetic factors. The objective of this study was to test the presence of the CYP2C9*3 allelic variant in the Chinese population and to investigate the association of this variant with both metabolism and therapeutic efficacy of irbesartan on essential hypertension. Methods In this study, we enrolled 711 subjects from Taihu County and 376 subjects from Dongzhi County in Anhui Province, China. All subjects received a single oral dose of 150 mg irbesartan daily for 28 days. The plasma concentration of irbesartan at 24 h after dosing on the 27th day and at 6 h after dosing on the 28th day was detected using fluorescence-high-performance liquid chromatography. CYP2C9 genotypes were determined using polymerase chain reaction—restriction fragment length polymorphism. Results No CYP2C9*2 allele was found in 235 Chinese samples and was removed from further study. The mean frequency of the CYP2C9*3 allele was 3.65%, while no CYP2C9*3/*3 genotype was detected. Multiple linear regression analyses revealed that the CYP2C9*3 allele carriers had significantly higher irbesartan concentrations in plasma at 6 h (Taihu: P<0.0001; Dongzhi: P=0.03) and 24 h (Taihu: P<0.0001; Dongzhi: P=0.00013) after dosing. No significant association was found between the CYP2C9*3 allelic variant and the therapeutic effect of irbesartan on essential hypertension. Conclusion Our study suggests that the CYP2C9*3 plays an important role in the metabolism of irbesartan and/or is in linkage disequilibrium with another potential CYP2C9 allele, both of which possibly modify the pharmacokinetics of irbesartan.     

Lack of Association between the Serotonin Transporter (5-HTT) and Serotonin Receptor (5-HT2A) Gene Polymorphisms with Smoking Behavior among Malaysian Malays

An insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and a polymorphism (rs6313) in the serotonin 2A receptor gene (5-HT2A) have previously been linked to smoking behavior. The objective of this study was to determine the possible association of the 5-HTTLPR and 5-HT2A gene polymorphisms with smoking behavior within a population of Malaysian male smokers (n=248) and non-smokers (n=248). The 5-HTTLPR genotypes were determined using the polymerase chain reaction (PCR) and were classified as short (S) alleles or long (L) alleles. The 5HT2A genotypes were determined using PCR-restriction fragment length polymorphisms (PCR-RFLP). No significant differences in the distribution frequencies of the alleles were found between the smokers and the non-smokers for the 5-HTTLPR polymorphism (x² = 0.72, P>0.05) or the 5HT2A polymorphism (x² = 0.73, P>0.05). This is the first study conducted on Malaysian Malay males regarding the association of 5-HTTLPR and 5HT2A polymorphisms and smoking behavior. However, the genes were not found to be associated with smoking behavior in our population.     

Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease

Aliment Pharmacol Ther 2011; 34: 1159–1172

Summary

Background Only a minority of alcoholics develop alcoholic liver disease (ALD) and allelic variants within genes encoding glutathione‐S‐transferases (GST) have been associated with ALD vulnerability with controversial results. Aim To assess the effects of GST polymorphisms on ALD by means of a genetic association study and meta‐analysis. Methods We retrieved published studies on the relationship between allelic variants within GST genes and ALD by means of electronic database search. A meta‐analysis was conducted in a fixed or random effects model. Calculations of odds ratios (OR) and their confidence intervals (CI), tests for heterogeneity of the results and sensitivity analysis, have been performed. A genetic association study comparing GSTM1, GSTT1 and GSTP1 genotype distribution among 279 alcoholics with or without ALD and 144 controls was also performed. Results Fifteen previous studies were identified analysing the association of ALD with polymorphisms within GST genes. After meta‐analysis, we found a significant association between the possession of the GSTM1 null allele and the presence of ALD (OR = 1.43; 95% CI: 1.14, 1.78; P = 0.002) among alcoholic patients. A significant association was also found for the possession of the GSTP1 Val/Val genotype and the presence of ALD (OR = 2.04; 95% CI: 1.09, 3.80; P = 0.03). Conclusions Our results suggest that, among alcoholics, carriers of GSTM1 null genetic variant or Val/Val genotype of Ile/Val GSTP1 polymorphism have an increased risk to suffer from alcoholic liver disease. The role of glutathione‐S‐transferase as a potential therapeutic target in alcoholic liver disease is reinforced.     

Effect of angiotensin-converting enzyme insertion/deletion genotype on collagen type I synthesis and degradation in patients with atrial fibrillation and arterial hypertension

Objective: The present study was undertaken to assess the impact of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphisms on circulating markers of collagen type I synthesis and degradation, and also to study the effect of therapy with ACE inhibitors on these markers in hypertensive patients with atrial fibrillation (AF). Research design and methods: ACE I/D genotypes were assessed in 158 hypertensive patients (71 ± 9 years; 72 male) with AF and 174 patients with arterial hypertension in sinus rhythm (SR) (71 ± 9 years; 88 male). Serum concentrations of amino-terminal propeptide of pro-collagen type I (PINP) and of carboxy-terminal telopeptide of collagen type I (CITP), indices of collagen type I synthesis and degradation, respectively, were measured. Results: Of the 332 study participants, 74 (22.3%) were I/I, 158 (47.6%) were I/D and 100 (30.1%) were D/D carriers. Genetic variation in ACE significantly influenced serum CITP levels in AF patients (p = 0.011). CITP levels were lower in D allele carriers (DD and ID) compared with I/I carriers. There was no difference in PINP levels between the different ACE genotype groups (p = 0.302). Patients treated with ACE inhibitors had higher CITP levels compared with those not treated (p = 0.036). Conclusions: This study suggests that the presence of the D allele in hypertensive patients with AF is associated with attenuation of type-I collagen degradation, and that therapy with ACE inhibitors increases degradation of collagen type I. The data indicate a subgroup of patients with AF and arterial hypertension who may benefit to a greater extent from therapy with ACE inhibitors, thus, providing a basis for pharmacogenetics.     

Cytochrome P450 2J2 Polymorphism in Healthy Caucasians and those with Diabetes Mellitus

Objective: Cytochrome P450 (CYP) 2J2 plays an important role in the biosynthesis of the biologically active cis-epoxyeicosatrienoic acids. An allelic variant named CYP2J2*6, which encodes an enzyme that is almost inactive in the metabolism of arachidonic acid, has recently been described. We investigated the frequency of the CYP2J2*6 variant in a Caucasian population and the relationship between this polymorphism and the development of micro- and macrovascular complications and hypertension in patients with type 1 or type 2 diabetes mellitus. Methods: Genomic DNA was extracted from peripheral blood cells and the fragment containing the A/T single nucleotide polymorphism at position 25 661 in exon 8 of the CYP2J2 gene was amplified. The 532 bp amplified product was subsequently digested with Tsp509I and analyzed on 12% polyacrylamide gel electrophoresis. Results: In the whole population, the frequency of the CYP2J2*6 allele was 0.0064 and the frequency of the CYP2J2*1 allele was 0.9936. Genotype distribution did not show significant differences between controls and patients with type 1 or type 2 diabetes. No homozygotes for CYP2J2*6 allele were found. No association was found between this allele and complications or hypertension in either type of diabetes. Conclusion: The CYP2J2*6 allele is rare in the Caucasian population, and no association is inferred between this allelic variant and diabetic complications.     

Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder

The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods.     

The ACE insertion/deletion polymorphism and risk of cancer, a review and meta-analysis of the literature

The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system. In addition to RAS enzymes in plasma, the RAS is present in various local organ systems. Moreover, local expression of the RAS has been shown in various malignant cells. In 1990, an insertion/deletion (I/D) polymorphism in the ACE gene was discovered, accounting for half of the variance of the serum ACE enzyme levels. Serum ACE concentrations were significantly higher in homozygotes with the shorter deletion allele (DD) than in heterozygotes (ID) or in homozygotes with the longer insertion allele (II). Since 2000, twenty-four studies have been published hypothesizing an association between the ACE I/D polymorphism and cancer risk. This review focuses on the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Furthermore a meta-analysis of the published studies was performed. Fourteen statistically non-significant studies were found, as well as ten studies with a statistically significant finding. The results of the meta-analyses performed were not consistent. However, both methods (one based on the Fisher p-value, and one on inverse variance weighted meta-analysis), indicated a (nearly) statistically significantly decreased risk in carriers of the II genotype in comparison to the DD genotype with regard to risk of prostate cancer and risk of (postmenopausal) breast cancer. Nevertheless, results show a large variation and are often contradictory. As this may be partly explained by a lack of power, genotyping techniques, and choice of study population, it is expected that future studies will shed more light on these associations.     

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.     

Hydrochlorothiazide efficacy and polymorphisms in ACE, ADD1 and GNB3 in healthy, male volunteers

Objective The antihypertensive effect of thiazide diuretics has recently been associated with genetic variation in the angiotensin I-converting enzyme (ACE), alpha-adducin (ADD1) and the G protein subunit β3 (GNB3). Analysis of short-term diuretic effects may provide insight into the mechanisms behind these findings. Methods A total of 103 male volunteers took 25 and 100 mg hydrochlorothiazide (HCT) after a placebo day, each. We measured volume, sodium, chloride, potassium, calcium excretion, blood pressure and heart rate. Results Excretion and cardiovascular parameters were highly constant between the 2 placebo days. The resting heart rate was 2–3 beats/minute (bpm) higher per ACE insertion allele on all 4 study days. The HCT-induced excretion of sodium, chloride and volume was independent of the genotypes. The additional potassium excretion induced by 100 mg HCT was 44±21, 33±27 and 16±26 mmol (mean±SD, p<0.001) in ACE II, ID and DD carriers and the same trend was observed after 25 mg HCT. As a second finding, the 100 mg HCT-induced calcium retention was 0.2±1.2, 0.7±0.8 and 1.7±2.1 mmol in ADD1 Gly/Gly, Gly/Trp and Trp/Trp carriers (p=0.002) and the same trend existed after 25 mg HCT. Conclusion The effects of genetic polymorphisms were stronger with the higher diuretic dose. ACE insertion allele carriers appeared to be more prone to hypokalaemia than deletion allele carriers. ADD1 Trp460 carriers may especially benefit from the calcium-sparing effect of thiazides. Both associations should be further studied in long-term treatment with thiazide diuretics.     

Rare Alleles within the CYP2E1 (MEOS System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Genetic polymorphisms influence the metabolism of ethanol and methanol, but the potential effects of genetic predisposition on the clinical course, outcome and short‐term health sequelae of acute methanol poisoning are unknown. To evaluate the role of the MEOS system in methanol poisoning, we analysed the effect of three polymorphisms (RsaI – rs2031920; PstI – rs3813867; insertion/deletion I/D) within the CYP2E1 enzyme (MEOS system) in 50 adult survivors of methanol poisoning and compared their genotype frequencies with 460 controls. The minor allele frequencies of all three polymorphisms were below 5% in both groups. We did not detect significant differences in the genotype frequencies between survivors of methanol poisoning and controls (p = 0.34 for the RsaI variant; p = 0.59 for the PstI variant and p = 0.21 for the I/D polymorphism). The carriers of at least one minor allele in the CYP2E1 gene had less severe clinical symptoms and better short‐term outcome after acute poisoning. Variants within the CYP2E1 gene are likely not significant genetic determinants of acute methanol poisoning (if survivors are analysed), but they may influence the severity of methanol poisoning and its visual/central nervous system (CNS) outcome.     

Association of OPRM1 A118G variant with the relative reinforcing value of nicotine

Rationale The endogenous opioid system has been implicated in substance abuse and response to pharmacotherapies for nicotine and alcohol addiction. We examined (1) the association of the functional OPRM1 A118G variant with the relative reinforcing value of nicotine and (2) the main and interacting effects of the mu-opioid receptor antagonist naltrexone on nicotine reinforcement.Methods In a within-subject, double-blind human laboratory study, 30 smokers of each OPRM1 genotype (A/A vs. A/G or G/G) participated in two experimental sessions following 4 days of orally administered naltrexone 50 mg or placebo. Participants completed a validated assessment of the relative reinforcing value of nicotine. This cigarette choice paradigm assesses self-administration of 0.6 mg nicotine vs. 0.05 mg (denicotinized) cigarettes after a brief period of nicotine abstinence.Results The relative reinforcing value of nicotine (number of nicotine cigarette puffs) was predicted by a significant OPRM1 by gender interaction. Among women, the low-activity G allele (A/G and G/G) was associated with a reduced reinforcing value of nicotine; among male smokers, there was no association with genotype. Smokers carrying a G allele were also significantly less likely to differentiate the nicotine vs. denicotinized cigarettes by subjective ratings of satisfaction and strength. No evidence for an effect of naltrexone on nicotine reinforcement was found in the overall sample or in the genotype or gender subgroups.Conclusions This study provides initial evidence for an association of the OPRM1 A118G variant with nicotine reinforcement in women.This research was supported by grants from the National Institute on Drug Abuse (RO1 DA017555-03) and National Cancer Institute (P50 CA/DA84718) (C.L.) and funding from the Commonwealth of Pennsylvania.