Interaction between TPH1 and GNB3 genotypes and electroconvulsive therapy in major depression.

We studied the association between tryptophan hydroxylase 1 (TPH1) A218C and G-protein beta-3 subunit (GNB3) C825T polymorphisms and treatment response in electroconvulsive therapy (ECT). The sample consisted of 119 patients with major depressive disorder (MDD) and 398 controls. Neither TPH1 nor GNB3 polymorphisms are associated with treatment response. However, subjects carrying TPH1 CC genotype are more likely to belong to the patient sample than to the controls. In female subjects, T-allele of GNB3 polymorphism increases the risk of being a treatment-resistant patient with MDD. Moreover, in females the combination of TPH1 CC and GNB3 CT + TT genotype is associated with an increased risk of belonging to the patient group.

RGS4 genotype is not associated with antipsychotic medication response in schizophrenia.

The aims of the present study were to compare the allele frequencies of a common single nucleotide polymorphism located upstream of the regulator of G-protein signaling 4 (RGS4) gene (T > G, Rs 951436) in 219 Finnish patients with schizophrenia and in 389 control subjects, to analyze corresponding frequencies between two different subtypes of 93 schizophrenia patients according to their medication response, and to study the effect of this SNP on age at onset in schizophrenia. The RGS4 (T > G, Rs 951436) genotype was not associated with incidence or age at onset in schizophrenia. Neither was the RGS4 genotype associated with medication response with two different subpopulations with schizophrenia.

Problems associated with biological markers of Alzheimer's disease.

The etiopathogenesis of Alzheimer's disease (AD) is still unclear, although clinical diagnostic criteria exist and the neuropathology of AD has been studied in great detail during the last 20 years. The present study addresses certain problems in the search for biological markers for the diagnosis, as well as in the follow-up of the course of AD and its differential diagnosis and reports some of our own observations in comparison with other studies. These include protein, genetic and neuroimaging markers. The definitions of biological markers and search strategies are also discussed.

Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics.

Several studies have connected brain-derived neurotrophic factor (BDNF) with treatment response to neuroleptics. In recent studies, the BDNF expression was reduced by typical neuroleptics. We conducted a retrospective study on 94 patients with schizophrenia and 98 controls. The BDNF G196A and C270T polymorphisms are not associated with treatment response to typical neuroleptics or with age at first hospitalization. Moreover, these polymorphisms of the BDNF gene are not associated with the risk of schizophrenia.

Lack of association between an estrogen receptor 1 gene polymorphism and Parkinson's disease with dementia.

OBJECTIVE: To test for an association between an estrogen receptor 1 (ESR1) gene polymorphism and Parkinson's disease with dementia (PDD) in Finnish subjects. SUBJECTS AND METHODS: Forty-one clinically demented and pathologically confirmed PDD patients and 59 cognitively intact aged individuals with normal neuropathology were genotyped for the ESR1 PvuII polymorphism. RESULTS: We found no significant differences in the genotype or allele frequencies when the PDD patients were compared with the controls. Nor were there any significant differences in these frequencies when the PDD patients with coexisting Alzheimer's disease pathology were compared with the control group. CONCLUSION: We failed to demonstrate an association between dementia-associated PD and the ESR1 PvuII polymorphism in Finnish subjects.

Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men.

BACKGROUND: Oxidised low-density lipoprotein (ox-LDL) is a determinant of impaired coronary function and oestrogens inhibit its formation probably throughout genetically-variable oestrogen receptor 1 (ESR1) in artery wall. We hypothesized that the ESR1 polymorphism might influence coronary function and reactivity as measured by positron emission tomography (PET), which allows the detection of coronary dysfunction before appearance of angiographic lesions. MATERIALS AND METHODS: Fifty-one healthy young men (aged 35 +/- 4 years), with normal or slightly-elevated serum cholesterol, underwent PET with intravenous adenosine. ESR1 PvuII genotypes P/P, P/p, and p/p in addition to the plasma autoantibody titre against ox-LDL, a marker of in vivo oxidation, were determined. RESULTS: The ESR1 genotype persisted as the only significant predictor of adenosine stimulated coronary flow (P = 0.035) after adjustment for other coronary risk factors. Subjects with P/P genotype had 33.4 and 41.8% lower adenosine-stimulated flow values than subjects with P/p and p/p genotypes (P = 0.030). Furthermore, plasma levels of ox-LDL titre were on average 59 and 77% higher in subjects with P/P genotype than in subjects with P/p or p/p genotypes (P = 0.049). CONCLUSIONS: These tentative findings from our pilot study provide evidence that genetic variation in ESR1 may modify coronary reactivity and LDL oxidation and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men.

Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study.

Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged >/=53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype.

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology.

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E epsilon4 allele (APOE epsilon4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE epsilon4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and epsilon4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and epsilon4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and epsilon4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and epsilon4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with epsilon4 had a combined effect with regard to the risk of AD.

Interaction between estrogen receptor 1 and the epsilon4 allele of apolipoprotein E increases the risk of familial Alzheimer's disease in women.

Estrogens may be implicated in the development of Alzheimer's disease (AD). Most of their effects are mediated via receptors whose function and expression may be modified by DNA polymorphisms. Here the estrogen receptor 1 gene (ESR1) polymorphisms XbaI and PvuII were analyzed in 214 AD patients and 290 controls. In logistic regression analysis, a significantly increased risk of familial AD due to interaction between the ESR1 xx genotype and the apolipoprotein E epsilon4 allele was observed in women in a Swedish clinic-based sample, taking subjects who had neither the xx genotype nor epsilon4 as reference (OR 11.3, 95% CI 2.9-43.8). The risk of AD was more pronounced in early-onset (OR 22.0, 95% CI 3. 7-132.7) than in late-onset (OR 6.0, 95% CI 1.2-29.7) female patients. For women carrying the pp genotype together with epsilon4 the risk of AD was similarly elevated. Likewise in a Swedish community-based set of women, an increased risk of familial AD was observed in subjects who had either the ESR1 xx or pp genotype together with epsilon4. Furthermore, the Pp genotype frequency was found to be significantly increased in Finnish women with sporadic AD. We, thus, conclude that the ESR1 gene may have a role in the development of AD in females.

The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease.

In early-onset familial Alzheimer's disease (AD) pathogenic mutations have been found in the amyloid precursor protein (APP) gene and in the presenilin (PS)-1 and PS-2 genes. We screened for mutations in these genes in 20 patients with familial AD from the Finnish population. In addition, we sampled 41 sporadic AD patients and 59 controls to test for mutations identified in our familial AD cases. We detected an A-to-G transition in the PS-1 gene, resulting in a glutamic acid (Glu)-to-glycine (Gly) substitution at codon 318 in 2 familial and 2 sporadic AD patients. The Glu318Gly mutation has previously been reported to cause AD. We also found the Glu318Gly mutation in 4 healthy aged controls (range, 74-87 years). We thus conclude that the mutation is most likely a rare polymorphism not related to AD.

Two-dimensional analysis of qualitative and quantitative changes in blood cell proteins in Alzheimer's disease: search for extraneuronal markers.

Numerous abnormalities have been reported to exist in tissues outside the central nervous system in Alzheimer's disease (AD), supporting the conception of the illness as a systemic disorder. Two-dimensional (2-D) polyacrylamide gel electrophoresis with an immobilized pH gradient of 4-8 in the first dimension combined with computer-assisted image analysis was applied in investigation of extraneuronal proteins of blood cell origin in AD to search for extraneuronal markers. No qualitative protein changes specific for the condition could be observed. However, many statistically significant quantitative alterations were detected when AD and control 2-D patterns of extracts prepared from red blood cell membranes, platelets and lymphocytes were compared. One of these spots, with a marked change in mean intensity value, was identified as actin. The concentration of this protein was significantly reduced in AD platelets and lymphocytes.

Alzheimer brain proteins investigated by two-dimensional gel electrophoresis with immobilized pH gradients in the first dimension.

Two-dimensional (2-D) gel electrophoresis with immobilized pH gradient 4-8 in the first dimension was applied in the analysis of Alzheimer's disease brain proteins. The silver-stained 2-D maps of extracts from the frontal cerebral cortex were examined. About 800 and 550 protein spots could be observed on the electrophoretograms from the total and buffer-soluble fractions, respectively. In comparing the gels, four protein spots could now be detected which had either been hitherto undetectable (one spot) or which were weaker (two spots) or stronger (one spot) in density (in the controls) [corrected].

Altered blood-brain-barrier function in Alzheimer's disease?

Alzheimer's disease (AD) and vascular dementia (VD) are the two most common causes of dementia. As yet, no definitive biological antemortem marker has been established for differential diagnosis of AD or VD. In this study, proteins of cerebrospinal fluid (CSF) from AD, VD and control patients were analyzed by two-dimensional (2-D) electrophoresis with immobilized pH gradients in the first dimension. No specific changes for AD or VD could be detected in the 2-D CSF patterns. However, a spot of haptoglobin alpha-1 chains (13.5 kDa; approximate pI 4.6) was found to be present in the majority of 2-D CSF maps from the dementia cases, suggesting a high-molecular-weight transudate type of alteration in the blood-brain barrier with considerable frequency in AD.