Publications by authors named "Kari M Mattila"

26 Publications

  • Page 1 of 1

Effects of Alzheimer's disease-associated risk loci on cerebrospinal fluid biomarkers and disease progression: a polygenic risk score approach.

J Alzheimers Dis 2015 ;43(2):565-73

Institute of Clinical Medicine - Neurology, University of Eastern Finland, and Department of Neurology, Kuopio University Hospital, Kuopio, Finland Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.

Background: Several risk loci for Alzheimer's disease (AD) have been identified during recent years in large-scale genome-wide association studies. However, little is known about the mechanisms by which these loci influence AD pathogenesis.

Objective: To investigate the individual and combined risk effects of the newly identified AD loci.

Methods: Association of 12 AD risk loci with AD and AD-related cerebrospinal fluid (CSF) biomarkers was assessed. Furthermore, a polygenic risk score combining the effect sizes of the top 22 risk loci in AD was calculated for each individual among the clinical and neuropathological cohorts. Effects of individual risk loci and polygenic risk scores were assessed in relation to CSF biomarker levels as well as neurofibrillary pathology and different biochemical measures related to AD pathogenesis obtained from the temporal cortex.

Results: Polygenic risk scores associated with CSF amyloid-β42 (Aβ42) levels in the clinical cohort, and with soluble Aβ42 levels and γ-secretase activity in the neuropathological cohort. The γ-secretase effect was independent of APOE. APOE-ε4 associated with CSF Aβ42 (p < 0.001) levels. For the other risk loci, no significant associations with AD risk or CSF biomarkers were detected after multiple testing correction.

Conclusions: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-140777DOI Listing
July 2015

Genetic loci associated with Alzheimer's disease and cerebrospinal fluid biomarkers in a Finnish case-control cohort.

PLoS One 2013 3;8(4):e59676. Epub 2013 Apr 3.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, The Netherlands.

Objectives: To understand the relation between risk genes for Alzheimer's disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish cohort with single nucleotide polymorphisms (SNPs) from top AlzGene loci, genome-wide association studies (GWAS), and candidate gene studies; and tested the correlation between these SNPs and AD markers Aβ(1-42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF).

Methods: We tested 25 SNPs for genetic association with clinical AD in our cohort comprised of 890 AD patients and 701-age matched healthy controls using logistic regression. For the correlational study with biomarkers, we tested 36 SNPs in a subset of 222 AD patients with available CSF using mixed models. Statistical analyses were adjusted for age, gender and APOE status. False discovery rate for multiple testing was applied. All participants were from academic hospital and research institutions in Finland.

Results: APOE-ε4, CLU rs11136000, and MS4A4A rs2304933 correlated with significantly decreased Aβ(1-42) (corrected p<0.05). At an uncorrected p<0.05, PPP3R1 rs1868402 and MAPT rs2435211 were related with increased t-tau; while SORL1 rs73595277 and MAPT rs16940758, with increased p-tau. Only TOMM40 rs2075650 showed association with clinical AD after adjusting for APOE-ε4 (p = 0.007), but not after multiple test correction (p>0.05).

Conclusions: We provide evidence that APOE-ε4, CLU and MS4A4A, which have been identified in GWAS to be associated with AD, also significantly reduced CSF Aβ1-42 in AD. None of the other AlzGene and GWAS loci showed significant effects on CSF tau. The effects of other SNPs on CSF biomarkers and clinical AD diagnosis did not reach statistical significance. Our findings suggest that APOE-ε4, CLU and MS4A4A influence both AD risk and CSF Aβ1-42.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059676PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616106PMC
October 2013

Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis.

Am J Med Genet B Neuropsychiatr Genet 2010 Jan;153B(1):235-42

Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain-derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimer's disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (P = 0.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (P = 0.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta-analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratio = 1.14, 95% CI 1.05-1.24, P = 0.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.30986DOI Listing
January 2010

RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder.

Neurosci Lett 2008 May 28;437(1):25-8. Epub 2008 Mar 28.

University of Tampere, Medical School, Department of Psychiatry, Tampere University Hospital, Tampere, Finland.

We studied the association between RGS4 (rs951436) polymorphism and treatment response in electroconvulsive therapy (ECT) as well as risk of treatment-resistant depression. The study sample consisted of 119 patients with major depressive disorder (MDD) and 384 healthy control subjects. RGS4 polymorphism was not associated with treatment response in ECT or risk of MDD. According to the present data, the impact of RGS4 genotype is not decisive in major depressive disorder. The results provide preliminary data on the impact of RGS4 polymorphism in treatment response in ECT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2008.03.065DOI Listing
May 2008

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia.

Eur Arch Psychiatry Clin Neurosci 2008 Feb 27;258(1):10-5. Epub 2007 Sep 27.

Dept. of Psychiatry, South Karelia Central Hospital, Valto Käkelän katu 14 C/6, Lappeenranta 53130, Finland.

Interleukin-1beta (IL-1beta) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1beta gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53-41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (chi(2) = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 +/- 7.7 and 22.7 +/- 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00406-007-0756-9DOI Listing
February 2008

Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia.

Hum Psychopharmacol 2007 Jun;22(4):211-5

University of Tampere, Medical School, and Tampere University Hospital, Department of Psychiatry, Finland.

Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hup.841DOI Listing
June 2007

Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia.

Neurosci Lett 2006 Oct 14;407(3):195-8. Epub 2006 Sep 14.

South Karelia Central Hospital, Department of Psychiatry, Lappeenranta, Finland.

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2006.08.041DOI Listing
October 2006

No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer's or Parkinson's disease.

Folia Neuropathol 2006 ;44(1):12-6

Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Center for Laboratory Medicine, Tampere University, Tampere, Finland.

The brain-derived neurotrophic factor (BDNF) promotes survival, differentiation and maintenance of neurons in the central nervous system. BDNF 196 G>A and 270 C>T polymorphisms have previously been associated with Alzheimer's disease (AD) and with Parkinson's disease (PD). To study the role of BDNF 196 G>A and 270 C>T polymorphisms in Finnish AD and PD patients we genotyped BDNF 196 G>A and 270 C>T polymorphisms in 97 sporadic AD patients, 52 PD patients and 101 control subjects with polymerase chain reaction. No associations were found between the genotypes studied and AD or PD in Finnish patients. Moreover, no interaction between either BDNF polymorphism and the epsilon 4 allele of apolipoprotein E was found. In conclusion, it seems that the BDNF gene does not contribute significantly to the risk of AD or PD in Finnish patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2006

High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.

Clin Pharmacol Ther 2005 Jul;78(1):60-8

Department of Internal Medicine, University Hospital of Tampere, Finland.

Background: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.

Methods: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.

Results: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.

Conclusions: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clpt.2005.03.006DOI Listing
July 2005

Tumor necrosis factor-alpha --G308A polymorphism in schizophrenia in a Finnish population.

Neurosci Lett 2005 Sep;385(1):76-81

South Karelia Central Hospital, Department of Psychiatry, Valto Käkelän katu 14C/6, FIN-53130 Lappeenranta, Finland.

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine with functions in nerve cell growth, differentiation, and apoptosis. There are several studies showing that a TNF-alpha--G308A promoter polymorphism, which possibly affects TNF-alpha transcription, is associated with schizophrenia, although negative results also exist. Our aim was to investigate the relationship between the TNF-alpha --G308A promoter polymorphism, the risk of schizophrenia, and the age of onset of schizophrenia, and the TNF-alpha -G308A polymorphism was therefore studied in 149 southern Finnish patients with a DSM-IV diagnosis of schizophrenia and in 393 healthy controls. The allele and genotype frequencies did not differ significantly between the patient and control groups (P=0.10 and 0.12, respectively), but the frequency of G/G homozygotes was statistically significantly higher in male patients than in male controls (chi(2)=5.03, d.f.=1, P=0.025) with an odds ratio of 2.00 (95% confidence interval: 1.08--3.70). No such difference was seen in female patients (P=0.79) or in the whole study group (P=0.064). The age of onset of schizophrenia did not differ significantly between the different TNF-alpha genotypes (ANOVA: F=0.45, P=0.64). In conclusion, we did not find a clear association between the TNF-alpha --G308A polymorphism and schizophrenia in the whole study group. However, TNF-alpha --G308A G/G homozygosity was modestly associated with schizophrenia in male patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2005.05.023DOI Listing
September 2005

Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques.

Atherosclerosis 2005 May 18;180(1):73-8. Epub 2004 Dec 18.

Laboratory of Atherosclerosis Genetics, FinnMedi-2, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland.

Objective: Matrix metalloproteinases 3 and 9 (MMP3 and MMP9) are present in atherosclerotic plaques and co-operate in the degradation of the fibrous cap of the atheroma, leading to fissuring and ultimately to acute coronary thrombosis. The functional genetic polymorphisms in the promoters of MMP3 and MMP9, which lead to low- and high-transcription activity genotypes, have been shown to be associated with myocardial infarction and angiographically measured atherosclerosis individually, whereas their effects in combination are not yet known. In order to assess the two disease loci simultaneously, we investigated the association of combined low and high promoter activity genotypes with different types of coronary lesions in an autopsy cohort of 300 Caucasian males aged 33-69 years (Helsinki Sudden Death Study).

Methods: Genotyping at these loci was performed by PCR, restriction enzyme digestion and minisequencing, and areas of the coronary wall covered with atherosclerotic lesions were measured using computer-assisted morphometry.

Results: In analysis of covariance (ANCOVA) with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, a significant interaction between the MMP3 and MMP9 genotypes was observed on area of complicated lesions (P=0.012). Men with high promoter activity genotypes for both loci had, on average, more than two times larger area of complicated lesions (250%) compared with those men who had low promoter activity genotypes (P=0.008), but these loci showed no association with myocardial infarction.

Conclusions: The joint action of two susceptibility loci, rather than single MMP genes alone, and the particular combination of MMP3 and MMP9 genotypes present at these loci may contribute to heterogeneity in the presentation of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2004.10.041DOI Listing
May 2005

The apolipoprotein E polymorphism is not associated with response to electroconvulsive therapy in major depressive disorder.

J ECT 2005 Mar;21(1):7-11

University of Tampere, Medical School, 33014 University of Tampere, Finland.

The apolipoprotein E (APOE) polymorphism is associated with neurodegenerative diseases. Its role regarding psychiatric disorders is controversial. It has been suggested to affect antidepressant treatment response and response to electroconvulsive therapy (ECT). In the present study, the association between APOE polymorphism and response to ECT in 119 patients with major depressive disorder was investigated. Moreover, a relation between APOE polymorphism and the age of onset of depression as well as the cognitive outcome of ECT was studied. In the whole population, no association was found between APOE polymorphism and response to ECT. However, in nonpsychotic patients, the epsilon2 allele tended to be more frequent in responders than nonresponders. Earlier onset of depression was observed in the patients with epsilon4 allele in late-life depression. There was no association between the APOE genotype and the cognitive change caused by ECT in the population as a whole. In women, however, epsilon2 allele may play a protective and epsilon4 allele a deleterious role in cognition during ECT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.yct.0000153210.25362.eaDOI Listing
March 2005

Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia.

Eur Arch Psychiatry Clin Neurosci 2005 Aug 24;255(4):279-83. Epub 2004 Dec 24.

University of Tampere, Medical School, 33014 Tampere, Finland.

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00406-004-0560-8DOI Listing
August 2005

Neuregulin genotype and medication response in Finnish patients with schizophrenia.

Neuroreport 2004 Nov;15(16):2517-20

University of Tampere, Medical School, Tampere, Finland.

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00001756-200411150-00017DOI Listing
November 2004

Interaction between matrix metalloproteinase 3 and the epsilon4 allele of apolipoprotein E increases the risk of Alzheimer's disease in Finns.

Neurosci Lett 2004 Sep;367(3):336-9

Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Center for Laboratory Medicine, Tampere University Hospital, PO Box 2000, FIN-33521, Finland.

Polymorphisms affecting the expression of matrix metalloproteinases (MMPs), i.e. proteolytic enzymes that degrade intercellular material, have been found at position -1607 (1G/2G) in MMP1 and at -1171 (5A/6A) in MMP3. Interestingly, elevated levels of MMP1 and MMP3 have been observed in the brains of Alzheimer's disease (AD) patients and those of tissue inhibitors of MMPs in the cerebrospinal fluid of AD and Parkinson's disease (PD) patients, suggesting a role for MMPs in these disorders. The aim was to investigate a possible association between the afore-mentioned MMP1 and MMP3 polymorphisms and the risk of developing AD or PD. The polymorphisms were genotyped in 97 AD, 52 PD and 101 control patients. We found an interaction between MMP3*5A and APOE 4 alleles (P < 0.0001) which increases the risk of AD (OR: 23.7, 95% CI: 5.8-144.9, P < 0.0001) compared to those who possess neither MMP3*5A nor APOE 4. In conclusion, our finding suggests that the MMP3 gene, especially together with APOE 4, may contribute to the development of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2004.06.027DOI Listing
September 2004

Apolipoprotein E polymorphism is associated with age of onset in schizophrenia.

J Hum Genet 2004 18;49(7):355-359. Epub 2004 Jun 18.

Medical School, University of Tampere, 33014, Tampere, Finland.

The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (epsilon 2, epsilon 3, and epsilon 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE epsilon 4/epsilon 4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of epsilon 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of epsilon 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE epsilon 4/epsilon 4 genotype may be associated with early onset schizophrenia. APOE epsilon 3 allele may function protectively in later onset in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10038-004-0157-0DOI Listing
August 2004

Association of EGF polymorphism with schizophrenia in Finnish men.

Neuroreport 2004 May;15(7):1215-8

University of Tampere, Medical School, Finland.

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00001756-200405190-00027DOI Listing
May 2004

Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics.

Pharmacogenetics 2004 May;14(5):303-7

University of Tampere, Medical School, 33014 University of Tampere, Finland.

Objective: In this study we attempted to show that the interaction between NOTCH4 and catechol-O-methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls.

Methods: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes (P = 0.003) and they have additive effect in treatment response.

Results: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007].

Conclusion: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00008571-200405000-00005DOI Listing
May 2004

Dopamine receptor D2 -141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia.

Psychiatry Res 2003 Nov;121(1):89-92

Department of Psychiatry, University of Tampere, Medical School, Tampere, FIN-33014, Finland.

We examined the occurrence of the -141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the -141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0165-1781(03)00201-4DOI Listing
November 2003

Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia.

J Clin Psychopharmacol 2003 Oct;23(5):429-34

Department of Psychiatry, Tampere University Hospital, Tampere, Finland.

Biogenic amine synthesis and degradation are involved in the pathogenesis of schizophrenia. Catechol-O-methyltransferase and monoamine oxidase enzymes are important agents in the metabolic inactivation of these neurotransmitters (ie, dopamine, serotonin, and norepinephrine). Functional polymorphism in the catechol-O-methyltransferase and monoamine oxidase A genes causes variation in enzyme activities. We investigated the relationship of catechol-O-methyltransferase Val158Met and monoamine oxidase A promoter repeat polymorphism with response to conventional neuroleptic treatment in schizophrenia.Ninety-four schizophrenic patients formed 2 different study populations. The responders had experienced a fair and steady response to conventional neuroleptics. The nonresponders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age-matched and gender-matched blood donors. Genotyping of the catechol-O-methyltransferase and monoamine oxidase A genes was performed by polymerase chain reaction.Forty-three percent of the nonresponders had a low activity catechol-O-methyltransferase genotype compared with 16% of the responders (P = 0.009). Monoamine oxidase A genotype alone did not differ significantly between the groups. Moreover, the risk of having both low-activity catechol-O-methyltransferase and monoamine oxidase A genotypes was over 6 times more common (odds ratio = 6.16, P = 0.03) in the nonresponders compared with responders. The whole population of patients with schizophrenia did not differ from the controls.The low-activity catechol-O-methyltransferase genotype may be associated with unsatisfactory drug response to conventional neuroleptics or alternatively be involved in a subset of schizophrenics. The role of monoamine oxidase A genotype seems to be additive in this respect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.jcp.0000088916.02635.33DOI Listing
October 2003

NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia.

Psychiatr Genet 2003 Jun;13(2):61-4

University of Tampere, Medical School, Tampereen yliopisto, Finland.

Objectives: The NOTCH4 gene has a promoter polymor-phism at position -25, which leads to the three genotypes TT, CT and CC. These have been suggested to present a novel independent genetic risk factor for schizophrenia. We conducted a prospective case-control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia.

Method: NOTCH4 gene promoter T-25C polymorphism was determined by polymerase chain reaction among 94 patients with schizophrenia and 94 healthy age-matched and sex-matched blood donors.

Results: The T allele was highly associated with an earlier age of onset in male patients of schizophrenia (Kaplan-Meier log-rank test P<0.0001). Moreover, the male patients carrying the T allele were born significantly more often in June-November compared with other months of the year [odds ratio=3.92 (95% confidence interval=1.025-15.018), P=0.046]. No association was determined, however, between the NOTCH4 gene polymorphism under study and schizophrenia.

Conclusion: The NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia and thus may be related to an early pathogenesis of schizophrenia in young patients. Alternatively, these findings may represent a significant genetic marker for managing subgroups and etiological clues in schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.ypg.0000056681.82896.6bDOI Listing
June 2003

Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics.

Eur Neuropsychopharmacol 2003 May;13(3):147-51

Tampere University Hospital, Department of Psychiatry, Tampere, Finland.

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0924-977x(02)00176-1DOI Listing
May 2003

The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women.

Maturitas 2003 Jan;44(1):29-38

Laboratory of Atherosclerosis Genetics, Center for Laboratory Medicine, University Hospital of Tampere, Finland.

Objective: The atheroprotective action of estrogen is mediated by estrogen receptors (ESR) 1 and 2, expressed in atherosclerotic lesions. The effects of hormone replacement therapy (HRT) and ESR1 PvuII genotypes on atherosclerosis have not previously been studied prospectively in postmenopausal women.

Methods: We investigated the effect of HRT on the progression of atherosclerosis in a 5-year follow-up study of 88 postmenopausal women aged 45-71 years at baseline allocated into three groups based on the use of HRT. The HRT-EVP group (n=26) used sequential estradiol valerate (EV) plus progestin (P), the HRT-EV group EV alone (n=32), and a control group (n=30) was without HRT. The atherosclerosis severity score (AS) of the abdominal aorta and carotid arteries were determined by sonography and the ESR1 PvuII genotypes (P/P, P/p and p/p) by PCR.

Results: HRT, time and ESR1 PvuII genotype had a statistically significant or borderline significant main effect on AS during 5-year follow-up (P=0.004, P<0.001 and P=0.090, respectively), when analyzed by repeated measures analysis of variance. There was a significant genotype-by-treatment (HRT-EVP and control groups) interaction for AS (P=0.034). In response to HRT-EVP, subjects with P/P, compared with those with P/p and p/p genotypes, had a less increase in AS (1.61+/-1.14 vs. 1.71+/-1.27 vs. 2.43+/-1.27). Baseline AS as covariate in similar model does not change the significant interaction effect between HRT-EVP and control groups (P=0.036). But this effect was not found between HRT-EV and control groups.

Conclusions: Our results suggest that the effect of HRT-EVP in postmenopausal women on progression of AS may be determined in part by the genotype of ESR1 PvuII.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0378-5122(02)00293-1DOI Listing
January 2003

Absence of association between an intercellular adhesion molecule 1 gene E469K polymorphism and Alzheimer's disease in Finnish patients.

Neurosci Lett 2003 Jan;337(1):61-3

Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, Finland.

Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0304-3940(02)01296-xDOI Listing
January 2003

Coronary artery calcification is related to functional polymorphism of matrix metalloproteinase 3: the Helsinki Sudden Death Study.

Atherosclerosis 2002 Oct;164(2):329-35

Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital, FinnMedi 2 3rd fl., PO Box 2000, FIN-33521, Tampere, Finland.

Matrix metalloproteinase 3 (MMP3) is expressed in human coronary atherosclerotic lesions and is known to be involved in degradation of the plaque and to be co-localized with calcium and fibrin deposits in advanced lesions, indicating a possible role of MMP3 in arterial calcification. The MMP3 gene promoter polymorphism leads to low promoter activity 6A6A, intermediate promoter activity 5A6A and high promoter activity 5A5A genotypes. To determine whether these genotypes predict the extent of atherosclerosis we investigated their association with different types of coronary lesions in an autopsy series of 300 middle-aged white Finnish men (aged 35-69 years) from the Helsinki Sudden Death Study (HSDS). Areas of the coronary wall covered with different atherosclerotic lesions were measured and MMP3 genotypes were determined by PCR and minisequencing. In men >/=53 years the mean area of calcified lesion in the most severely affected coronary artery was significantly associated with the MMP3 genotype (P=0.029). Subjects with high promoter activity genotypes had on average larger calcified lesion areas than those with the low-activity genotype. The MMP3 genotype (P=0.025) persisted as an independent predictor of mean calcified lesion area after stepwise adjustment for age, BMI, hypertension, diabetes, number of affected vessels and smoking. These data provide evidence that the proposed effect of MMP3 in the process of atherogenesis may be modified by the MMP3 genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0021-9150(02)00107-7DOI Listing
October 2002

Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study.

J Mol Med (Berl) 2002 Mar 17;80(3):176-80. Epub 2002 Jan 17.

Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Center for Laboratory Medicine and Medical School, Tampere University Hospital, P.O. Box 2000, 33521 Tampere, Finland.

Estrogen receptors (ESR) 1 and 2 are expressed in the normal and atherosclerotic arteries mediating the atheroprotective action of estrogen to artery wall cells. Whether variants of these receptor genes associate with autopsy-verified coronary artery wall atherosclerosis is not known. This study investigated whether variants of the ESR1 gene are associated with autopsy-verified coronary artery wall atherosclerosis and thrombosis. Coronary arteries were taken from 300 white Finnish male autopsy cases aged 33-69 years included in the Helsinki Sudden Death Study. Areas of coronary wall covered with fatty streaks, fibrotic, calcified, and complicated lesions were measured using computer-assisted planimetry and related to ESR1 PvuII genotypes (P/P, P/p, and p/p) determined by PCR. The mean area of complicated lesions of three major coronaries and the presence of coronary thrombosis were significantly associated with the ESR1 genotype in men aged 53 years or older (median age as a cut off point). No such association was found in men aged under 53 years. After adjusting for age and body mass index the men aged 53 years or over with P/p and P/P genotype had areas of complicated lesions on average two- and fivefold larger than subjects with the p/p genotype. The age and body mass index adjusted odds ratios for coronary thrombosis were 6.2 for P/p and 10.6 for P/P compared to men with the p/p genotype. After additional adjustment for diabetes and hypertension the ESR1 genotype persisted as an independent predictor of complicated lesions ( P=0.007) and coronary thrombosis. In conclusion, the ESR1 gene is a potential candidate behind the pathogenesis of acute coronary events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-001-0311-5DOI Listing
March 2002
-->