No Association Between Polymorphisms in the Human Dopamine D3 and D4 Receptors Genes and Alcoholism

The human dopamine D₂ receptor gene (DRD₂) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD₂ gene between alcoholics and control groups have produced equivocal results. Dopamine D₃ and D₄ receptor genes (DRD₃ and DRD₄) are in the same class as DRD₂ but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD₃ and DRD₄ genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD₃ and tandem repeat (VNTR) in DRD₄ genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD₃ and DRD₄ genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism. Am. J. Med. Genet. 74:281–285, 1997. © 1997 Wiley-Liss, Inc.     

Lack of association between obsessive-compulsive disorder and the dopamine D3 receptor gene: Some preliminary considerations

Controversial results possibly suggesting an association between Tourette's Syndrome (TS) and excess of homozygosity at a Msc I polymorphism in the Dopamine D₃ receptor (DRD₃) gene have recently been reported. Since a relationship between Obsessive-Compulsive Disorder (OCD) and Tourette's Syndrome (TS) has been suggested, in this study we assessed the frequency of this 2-allele polymorphism in a sample of 97 OCD patients and in 97 control subjects. No statistically significant differences in allele or genotype frequencies were found. Thus this mutation in the coding sequence of the DRD₃ gene is unlikely to confer susceptibility to OCD. © 1994 Wiley-Liss, Inc.     

Encomium: Theodore puck,a life in biophysics applied to medicine

The dopamine hypothesis of schizophrenia proposed that dopaminergic pathways are involved in the etiology of the disease. In particular, interest among psychiatrists has focused on the D₂ receptor because of its affinity to antipsychotic drugs. Recently a new dopamine receptor gene has been cloned, and named the dopamine D₃ receptor. The D₃ receptor is a potential site for antipsychotic drug action and may be involved in the pathophysiology of schizophrenia. We have carried out a linkage study between the susceptibility gene for schizophrenia and polymorphism of the dopamine D₃ receptor gene in two Japanese pedigrees. The LOD scores were negative for, all genetic models and for all affective status at a recombination fraction θ = 0. Linkage of DRD₃ has been excluded for the model 1 (dominant model) and the model13 (recessive model). The LOD score was - 3.43 at θ = 0 for model 1 (dominant model) and broad definition of affected status. These results were consistent with previous studies. © 1994 Wiley-Liss, Inc.     

Lack of association in Japanese patients between neuroleptic malignant syndrome and a debrisoquine 4-hydroxylase genotype with low enzyme activity

Decreased activity of debrisoquine 4-hydroxylase (CYP2D6), which participates in hepatic metabolism of several frequently used neuroleptics and antidepressants, is inherited as an autosomal recessive trait through polymorphic CYP2D6 gene alleles. In eastern Orientals, a C --> T substitution at nucleotide 188 (Pro34Ser) is primarily responsible for decreased ability to metabolize CYP2D6 substrates. We therefore studied a possible association between neuroleptic malignant syndrome (NMS) and the C188T mutation. We examined the frequency of the C188T mutation by polymerase chain reaction and restriction fragment length polymorphism analysis in 36 Japanese patients previously diagnosed with NMS and 107 neuroleptic-treated schizophrenic patients with no NMS history. The C188T allele frequency was 0.417 in NMS patients and 0.463 in patients without NMS. No significant allele or genotype associations were observed. We cannot conclude that low CYP2D6 activity genotype causes susceptibility to NMS in Japanese patients.     

Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case–control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case–control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: χ² = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: χ² = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48–0.88). However in a meta-analysis of nine Japanese case–control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel–Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97–1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.     

Association analysis of an (AC)n repeat polymorphism in the GABAB receptor gene and schizophrenia

The human γ‐aminobutyric acid type B (GABA_B) receptor gene is a candidate gene for schizophrenia due to its chromosomal location and neurobiologic roles. In the present study, association analyses of genetic polymorphisms of the GABA_B receptor gene with schizophrenia were carried out in 102 unrelated schizophrenic patients and 100 healthy controls, using a polymerase chain reaction‐based, single‐strand conformational polymorphism analysis. Although the Ala20Val and Gly489Ser mutations were not found in our samples, we found a novel polymorphism of (AC)n dinucleotide repeats located approximately 1.6 kb upstream from the translational start site. No significant difference in allele frequencies was found between controls and patients with schizophrenia (P = 0.0587) using the Monte Carlo method. Significant differences were found between controls and patients with continuous‐course schizophrenia (P = 0.0019), and between controls and patients with a positive family history of psychoses (P = 0.0015). These differences, however, were not significant after Bonferroni correction. These data did not support our hypothesis that polymorphisms of the GABA_B receptor gene may confer vulnerability for schizophrenia. © 2002 Wiley‐Liss, Inc.     

Studies of muscarinic receptor reserve linked to phosphoinositide hydrolysis in parotid gland and cerebral cortex

Hydrolysis of inositol phospholipids caused by muscarinic agonists was studied in the guinea-pig parotid gland (PG) and cerebral cortex (CX). The present study describes the effect of two muscarinic agonists, carbachol and oxotremorine, on stimulation of phosphoinositide hydrolysis and on binding of [³H]NMS in the presence of the irreversible muscarinic antagonist benzilyl choline mustard (BCM). Carbachol and oxotremorine stimulated the formation of inositol phosphates in PG, pD₂(Carb) = 5.3 ± 0.1, pD₂(Oxo) = 5.9 ± 0.1 and in CX, pD₂(Carb) = 4.3 ± 0.2, pD₂(Oxo) = 5.8 ± 0.2. In the present study slices from both tissues have been exposed to 0.1 μM BCM for 2, 5 and 10 min. Treatment for 10 min caused a 75–85%, reduction in specific [³H]N-methyl scopolamine ([³H]NMS) binding sites in both PG and CX. Following 2 min BCM treatment of PG a marked decrease in pD₂ value of the carbachol-stimulated inositol phosphate formation was found. This effect was not found in CX. The results showed that a 30–40% reduction in binding sites shifted the carbachol concentration response curve to the right by one order of magnitude and reduced the oxotremorine-induced release of inositol phosphates by approximately 20%. In PG, the BCM-induced reduction of the carbachol-stimulated inositol phosphate formation was paralleled by the reduction in receptor binding sites. Similar treatment, but in CX, showed a lower reduction of the carbachol-stimulated inositol phosphate formation as compared to the reduction in receptor-binding sites. The results from the present study indicate that stimulation of phosphoinositide hydrolysis in PG involves a receptor reserve, mainly via stimulation of M₂-muscarinic receptors.     

Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics

A dysfunction of dopaminergic neurotansmission has been implicated in alcohol-seeking behavior. Recently, a significant association between the seven-repeat allele (DRD4*7R) of a 16 amino acid motif in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait of novelty seeking has been reported. Our population-based association study tested the hypothesis that the DRD4*7R variant predisposes to high levels of novelty seeking, which may underlie alcohol-seeking behavior. The genotypes of the expressed DRD4 exon III polymorphism were determined in 197 German controls and 252 German alcohol-dependent males, of whom 92 alcoholics completed the tridimensional personality questionnaire. We found no significant differences in the DRD4*7R frequencies between controls and alcoholics, including two subgroups (56 alcoholics with dissocial personality disorder according to ICD-10 and 89 alcoholics with severe withdrawal symptoms) with a high level of novelty seeking. The novelty-seeking scores did not differ significantly between alcoholics (including both subgroups) carrying long alleles with six or more repeats compared with those lacking long alleles. The present results do not provide evidence that the DRD4*7R allele contributes a common and relevant effect to alcohol-seeking behavior in our sample of alcoholics. Am. J. Med. Genet. 74:483–487, 1997. © 1997 Wiley-Liss, Inc.     

No association between schizophrenia and homozygosity at the D3 dopamine receptor gene

The D₃ dopamine receptor gene is an important candidate gene for schizophrenia, since (because of its almost exclusive expression in the limbic system) it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. A BalI restriction fragment length polymorphism of the D₃ dopamine receptor gene has been typed in 107 schizophrenic patients and 98 normal controls from Sichuan (China). With regard to alleles or genotypes, no significant differences were obtained between controls from Europe and China, between patients and controls, and between patient subgroups and controls. These results indicate a lack of association between schizophrenia and the D₃ dopamine receptor gene in our sample. Our findings are at variance with reports of a significant excess of homozygosity at the D₃ dopamine receptor gene in schizophrenic patients from Wales (United Kingdom) and Alsace (France). In conclusion, further studies will be needed with larger samples of patients from Wales and Alsace as well as with samples of different racial groups to prove or disprove the initial positive association between schizophrenia and genotypes of the D₃ dopamine receptor gene. © 1993 Wiley-Liss, Inc.     

Neonatal Maternal Separation Disrupts Regulation of Sleep and Breathing in Adult Male Rats

Study Objectives:

Neonatal maternal separation (NMS) disrupts development of cardiorespiratory regulation. Adult male rats previously subjected to NMS are hypertensive and show a hypoxic ventilatory response greater than that of controls. These results have been obtained in awake or anesthetised animals, and the consequences of NMS on respiratory control during normal sleep are unknown. This study tested the following hypotheses: NMS augments respiratory variability across sleep-wake states, and NMS-related enhancement of the hypoxic ventilatory response occurs during sleep.

Methods:

Two groups of adult rats were used: controls (no treatment) and rats subjected to NMS. Ventilatory activity, coefficient of variation, and hypoxic ventilatory response were compared between groups and across sleep-wake states.

Subjects:

Male Sprague Dawley rats—NMS: n = 11; controls: n = 10. Pups subjected to NMS were isolated from their mother for 3 hours per day from postnatal days 3 to 12. Controls were undisturbed.

Measurements and results:

At adulthood, sleep-wake states were monitored by telemetry, and ventilatory activity was measured using whole-body plethysmography. Sleep and breathing were measured for 2.5 hours (in the morning) while the rats were breathing room air. Data were analysed in 20-second epochs. Rats were then exposed to a brief (90-sec) hypoxic episode (nadir = 12% O₂) to measure the hypoxic ventilatory response. The coefficient of variability for tidal volume and breathing frequency decreased during sleep but remained more elevated in NMS rats than in controls. During non-rapid eye movement sleep, the breathing-frequency response to hypoxia of NMS rats was significantly greater than that of controls.

Conclusion:

Neonatal maternal seperation results in persistent disruption of respiratory control during sleep.

Citation:

Kinkead R; Montandon G; Bairam A; Lajeunesse Y; Horner R. Neonatal maternal separation disrupts regulation of sleep and breathing in adult male rats. SLEEP 2009;32(12):1611-1620.     

D2 dopamine receptor polymorphism and brain regional glucose metabolism

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D₂ dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1⁺) compared with those who do not (A1⁻). In the present study, using ¹⁸F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1⁺ or A1⁻ allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1⁺ than the A1⁻ group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1⁺ group was also found in Broca's area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1⁺ group. Since polymorphism of the DRD² gene is commonly observed in humans, the importance of differentiating A1⁺ and A1⁻ alleles subjects in PET studies is suggested. Am. J. Med. Genet. 74:162–166, 1997. © 1997 Wiley-Liss, Inc.     

Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: Identification of a functional mutation in the promoter and a new coding variant (T21M)

To elucidate if genetic variants in the bradykinin B₂ receptor (B₂) gene occur that could affect receptor expression and function, we screened for mutations in the promoter and in the coding region of the human B₂ gene. In our initial study we analyzed 92 consecutive, unrelated subjects (including 25 patients with hypertrophic cardiomyopathy, 18 patients with dilated cardiomyopathy (DCM), 25 patients with hypertension, 18 patients with coronary heart disease, and 6 patients with valvular heart disease) using nonradioactive polymerase chain reaction–single-strand conformation polymorphism analysis as mutation screening method. We detected eight as yet unknown polymorphic sites in the promoter region of the B₂ gene (−845 C/T, −704C/T, −649 insG, −640 T/C, −536 C/T, −412 C/G, −143 C/T and −78 C/T) with allele frequencies between 0.5 and 13%. One of them (−412 C/G) destroys a Sp1 binding site and abolishes protein binding to this Sp1 site in human umbilical vein endothelial cells and human vascular smooth muscle cells. In the protein-coding region one new coding variant (T21M) with the potential to create a truncated receptor isoform was detected. We determined the frequency of the promoter variant at position −412 (C → G) and the newly identified coding variant (T21M) in extended samples of 69 patients with HCM, 163 patients with DCM, 109 patients with hypertension, and 173 healthy anonymous blood donors. The promoter variant (−412C/G) was found in one blood donor and the T21M mutation was not found in the control population. Therefore, it appears that these mutations are rare events and the determination of clinical significance will be a demanding task in the future. Am. J. Med. Genet. 80:521–525, 1998. © 1998 Wiley-Liss, Inc.     

Retinoid X receptor beta polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients

It has been suggested that the retinoid X receptor beta (RXRB) gene is a risk factor for Wegener's granulomatosis. We addressed if there is a functional difference in the response to retinoic acid (RA) and vitamin D in Antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV) patients and if this was associated with RXRB genotypes. TNFα and IL-10 production were measured in whole blood assay from AASV patients (n = 51) and healthy controls (HC, n = 67). One micromolar of 1,25-(OH)₂ D3, 9-cis RA (9c-RA) or all-trans RA (ATRA) was added to the assay. Genotyping was performed for exons 7 and 2 of the RXRB gene and for a microsatellite in vicinity of the RXRB gene. Lipopolysaccharide (LPS) mediated TNFα production and IL-10 were significantly lower in patients. Addition of 1,25-(OH)₂ D3, ATRA or 9c-RA, blunted TNFα production, more pronounced in patients. Although all three compounds inhibited IL-10 production significantly in HC, only 1,25-(OH)₂ D3 was found to be effective in patients. Allele distribution of the RXRB microsatellite differed significantly between patients and HC. This was not found for the SNP in exons 2 and 7. Genotype of the latter correlated with the ability of 1,25-(OH)₂ D3 and ATRA to inhibit IL-10 production. We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients. Since the inhibition of TNFα was more effective in patients, vitamin D supplementation might be an additional therapeutical approach.     

Association analysis of exonic variants of the gene encoding the GABAB receptor and idiopathic generalized epilepsy

The gene encoding the GABA_B receptor (GABA_BR1) maps close to the HLA-F locus on chromosome 6p21.3 in the same region to which a major susceptibility locus for common subtypes of idiopathic generalized epilepsy (IGE), designated as EJM1, has been localized. Moreover, animal models suggest that the GABA_B receptor plays a critical role in the epileptogenesis of absence seizures. Accordingly, the present association study tested the candidate gene hypothesis that genetic variants of the human GABA_BR1 gene confer susceptibility to common subtypes of IGE. Three DNA sequence variants in exons 1a1, 7, and 11 of the GABA_BR1 gene were assessed by PCR-based restriction fragment length polymorphisms in 248 unrelated probands of German descent, comprising 72 patients with juvenile myoclonic epilepsy (JME), 46 patients with idiopathic absence epilepsy (IAE), and 130 control subjects without a history of epileptic seizures and lack of generalized spike-wave discharges in their electroencephalogram. The results revealed no evidence for an allelic association of any of the GABA_BR1 sequence variants with either JME or IAE (P > 0.18). Thus, we failed to demonstrate that any of the three exonic GABA_BR1 variants themselves, or other so-far unidentified mutations, which are in strong linkage disequilibrium with the investigated variants, are involved in the pathogenesis of common IGE subtypes. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:305–310, 1999. © 1999 Wiley-Liss, Inc.     

Role of Baroreflex Sensitivity in Predicting Tilt Training Response in Patients with Neurally Mediated Syncope

PurposeAn association between baroreflex sensitivity (BRS) and the response to tilt training has not been reported in patients with neurally mediated syncope (NMS). This study sought to investigate the role of BRS in predicting the response to tilt training in patients with NMS.ResultsAfter tilt training, 52 patients (91.2%) achieved three consecutive negative responses to the HUT. In the supine position before upright posture during the first session of tilt training for responders and non-responders, the mean BRS was 18.17±10.09 ms/mm Hg and 7.99±5.84 ms/mm Hg (p=0.008), respectively, and the frequency of BRS ≥8.945 ms/mm Hg was 45 (86.5%) and 1 (20.0%; p=0.004), respectively. Age, male gender, frequency of syncopal events before HUT, type of NMS, phase of positive HUT, total number of tilt training sessions, and mean time of tilt training did not differ between the study groups. In the multivariate analysis, BRS <8.945 ms/mm Hg in the supine position (odds ratio 23.10; 95% CI 1.20-443.59; p=0.037) was significantly and independently associated with non-response to tilt training.ConclusionThe BRS value in the supine position could be a predictor for determining the response to tilt training in patients with NMS who are being considered for inpatient tilt training.     

Adrenaline induces chemoresistance in HT-29 colon adenocarcinoma cells

Psychological distress and its ensuing chronic elevation of plasma catecholamines (adrenaline and noradrenaline) lead to poor response of tumors to chemotherapy, and constitute a poor prognostic factor for survival. Colorectal cancer patients suffer from various forms of psychological stress reflected in elevated plasma catecholamines, and their cancer cells express adrenergic receptors. Our objective was to investigate whether adrenergic activation contributes to the chemoresistance of colon cancers, and to explore the signal transduction pathway involved in the activation. The mRNA expression of the ABCB1 gene (previously MDR1) in human colon carcinoma HT-29 cell line was measured after treatment with an adrenergic receptor agonist (adrenaline) and various antagonists (propranolol, prazosin, and yohimbine). The function of P-glycoprotein, the protein product of the ABCB1 gene, was assessed by rhodamine 123 (Rh123)–retention assay, and chemosensitivity was determined by evaluating the cytotoxicity of 5-fluorouracil (5-FU) on the tumor cells. Increased ABCB1 mRNA expression and P-glycoprotein function levels in HT-29 cells by adrenaline was dose-dependent. This was accompanied by promotion of Rh123 efflux, and resistance to the growth-inhibiting effect of 5-FU in the tumor cells. The α₂-adrenergic receptor antagonist yohimbine completely abolished the induction of ABCB1 mRNA, the stimulatory effect of adrenaline on Rh123 efflux, and the growth-inhibiting effect of 5-FU. The α₁-adrenergic receptor and β-adrenergic receptor antagonists did not inhibit the induction of ABCB1. The stimulating effects were coupled with extracellular receptor kinase 1/2 (Erk1/2) phosphorylation, but were not associated with protein kinase A activity. We conclude that adrenaline induces multidrug resistance in colon cancer cells by upregulating ABCB1 gene expression via α₂-adrenergic receptors, and such effects were associated with the mitogen activated protein kinase (MAPK) pathway.     

Activation via the antigen receptor is impaired in T cells,but not in B cells from patients with common variable immunodeficiency

The patients included in this study belong to a subset of common variabie immunodeficiency (CVID) patients whose peripheral blood T cells have a T cell receptor (TCR)-mediated activation defect leading to impaired expression of the interleukin (IL)-2 gene upon stimulation with recall antigens (tetanus toxoid, Escherichia coli) or superantigens (staphylococcal enterotoxins). In the present report we demonstrate that the patients' peripheral blood T cells failed to generate the second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) following stimulation with superantigen or mAb specific for the monomorphic region of the TCR β-chain. Patients' T cell lines were also impaired in generating Ins(1,4,5)P₃ when stimulated with tetanus toxoid-pulsed autologous monocytes. Addition of a second or third co-stimulatory signal provided by recombinant IL-2, CD28 or both had no effect on the Ins(1,4,5)P₃ formation of the patients' antigen-driven T cell lines. The T cell activation defect, however, was not absolute, as Ins(1,4,5)P₃ formation in the patients' T cells after phytohemagglutinin or aluminium fluoride stimulation was normal. The impairment in signal transduction via the T cell antigen receptor was limited to the patients' T cells, as no activation defect after ligation of surface immunoglobulin, the antigen receptor on B cells, could be detected.     

Renin gene and angiotensin II AT1 receptor gene expression in the kidneys of normal and of two-kidney/one-clip rats

This study aimed to investigate the inter-relation between the angiotensin II (ANG II) AT₁ receptor and renin gene expression in rat kidneys. To this end, renin mRNA levels and mRNA levels for AT_1a and AT_1b were assayed by RNase protection in the kidneys of normal rats, in animals treated with the AT₁ antagonist losartan and in rats bearing 0.2-mm left renal artery clips for 2 days. In normal rats, we found a negative correlation between renin mRNA levels and AT_1a receptor mRNA levels. Losartan led to a fourfold increase in renin mRNA levels without changing AT₁ receptor mRNA levels. Unilateral renal artery clipping increased renin mRNA levels fourfold in the clipped kidney and suppressed renin mRNA levels in the contralateral kidneys. AT₁ receptor mRNA levels were not changed in the contralateral intact kidneys, but were significantly decreased by 15–25% in the clipped kidneys. Renin mRNA levels were inversely correlated to AT_1a mRNA levels in the clipped, but not in the contralateral, kidneys. Our findings suggest that the systemic activity of the renin angiotensin system has no regulatory influence on renal AT₁ receptor gene expression. Renin mRNA levels in normal and in clipped kidneys appear to be negatively determined by the level of AT_1a receptor gene expression. Thus modulation of AT_1a receptor gene expression could be a pathway for indirect modulation of renin gene expression by ANG II. This conclusion is in agreement with the observation that AT₁ receptor antagonists are powerful stimulators of the renin system.     

MTHFR (methylenetetrahydrofolate reductase) C677T polymorphism and psoriasis

The aim of the study was to evaluate possible association of MTHFR C677T gene polymorphism (NM_005957) with psoriasis. Genotypes of MTHFR C677T gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. Case group (n = 410) included patients with psoriasis (plaque psoriasis diagnosed in 285 patients, other subtypes of psoriasis were observed in 125 patients). Control group (n = 244) consisted of healthy subjects without individual history of psoriasis, with similar age and gender characteristics. The MTHFR C677T polymorphism genotypes were determined by a polymerase chain reaction and a subsequent restriction analysis with HinfI. The genotypes of C(677)T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism were determined in a sample of 654 Caucasian (Czech) subjects. We proved a significant difference in genotype distribution (P _g = 0.03) and allelic frequency (P _a = 0.02) between psoriatic and control subjects (Table 3). The CC (the thermostabile) genotype was significantly more frequent in psoriatic patients compared to controls [OR = 1.55, 95% confidential interval (CI) = 1.12–2.15, P = 0.004814, P _corr = 0.01]. But, a significant increase of T allele in MTHFR gene was observed in patients with positive family history of diabetes (P _a = 0.02) and in those with a frequent tonsillitis/tonsillectomy (P _a = 0.04). No difference was observed between patients with and without positive family history of psoriasis (P _a = 0.251). But, when psoriatic patients were described for FHDM, FH-Ps, and PH-T simultaneously, The highest incidence of CT + TT genotypes was calculated for psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy compared to patients without all these three phenotypes (odds ratio = 3.17, 95% CI 1.33–7.56, P _corr = 0.04). In conclusion, MTHFR C677T polymorphism is marginally associated with psoriasis. The T allele (thermolabile) appears to be more frequent in psoriasis patients with positive history of psoriasis and diabetes mellitus together with personal history of repeated tonsillitis/tonsillectomy. This could reflect an inborn predisposition in complex regulation in one-carbon moieties transport in psoriatic patients and therefore, MTHFR genotype can be a part of genetic background of psoriasis.     

Analysis of the Linkage of the Taq1A and Taq1B Loci of the Dopamine D2 Receptor Gene with Schizophrenia in Patients and Their Siblings

The linkage of the polymorphous markers Taq1A and Taq1B of the DRD2 dopamine receptor gene, located in region 11q22-11q23 of chromosome 11, with schizophrenia was studied. The investigation involved 29 complete families containing concordant and discordant sibling pairs. Common alleles at locus Taq1A were found significantly more frequently in concordant pairs (p = 0.04), and there was a tendency to a higher frequency of transmission of the maternal allele as compared with the paternal allele (p = 0.06). No such relationships were seen in the case of the Taq1B locus. Neither locus showed any significant difference in the frequency of common alleles in discordant pairs or in the predominance of allele transmission from one of the parents. These data demonstrate a possible linkage with schizophrenia for the Taq1A marker but not for the Taq1Bmarker.