Association of CYP46 intron 2 polymorphism in Finnish Alzheimer's disease samples and a global scale summary.
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Biomedical subjects
S Helisalmi
Publications and source records attributed to S Helisalmi.
Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice.
The brain is an important target organ for peripherally synthesized estrogen but it also has its own steroid biosynthesis producing estrogen from testosterone catalyzed by the aromatase enzyme. This study examined the effects of estrogen treatment in two spatial memory tasks, one-arm-baited radial arm maze and a position discrimination task in the T-maze in ovariectomized female mice. Hippocampal cytochrome P450 19 (encoding aromatase), and estrogen receptor alpha and beta gene expressions were also measured using real time quantitative polymerase chain reaction analysis. Estrogen (17beta-estradiol) was administered either tonically via s.c. minipellets or phasically via daily i.p. injections. In ovariectomized mice, the tonic estrogen decreased the number of reference memory errors in radial arm maze. Tonic estrogen treatment also up-regulated the expression of cytochrome P450 19 and estrogen receptors. In contrast, estrogen injections decreased the expression of cytochrome P450 19 and estrogen receptor alpha genes. The number of reference memory errors correlated negatively with estrogen receptor alpha expression. These findings indicate that peripheral estrogen levels affect neuronal estrogen synthesis by regulating the cytochrome P450 19 gene expression and also influence estrogen receptor alpha expression. The results also suggest that tonic rather than cyclic estrogen treatment might be more beneficial for cognitive functions.
Animals↗
Possible association of nicastrin polymorphisms and Alzheimer disease in the Finnish population.
The authors previously reported that genetic variation in the gene coding for nicastrin (NCSTN) modified risk for familial early-onset Alzheimer disease (AD) in a Dutch population-based sample. Risk was highest in patients without an APOE epsilon4 allele. Here, they evaluated if NCSTN polymorphisms increased risk of AD in the eastern Finnish population. A significant difference in one haplotype was observed in AD patients without the APOE epsilon4 allele.
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Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease.
BACKGROUND: Brain aromatase may be neuroprotective by increasing the local estrogen levels in injured neurons. Aromatase is encoded by the CYP19 gene located at 15q21.1, a chromosomal region in linkage disequilibrium (LD) with Alzheimer disease (AD) in this sample. OBJECTIVE: To investigate whether nine single-nucleotide polymorphisms (SNP) spanning the CYP19 gene were associated with AD. METHODS: Three hundred ninety-four patients were compared with 469 nondemented control subjects using single-locus and haplotype approaches. Haplotypes were identified using the expectation/maximization algorithm and latent class analysis, which included additional information on age, sex, and APOE polymorphism. RESULTS: Allelic and genotypic frequencies for three adjacent SNP differed between AD and control groups. Both haplotype approaches identified an approximately 60% increase (p = 0.02) in the risk of AD for one haplotype and similar levels of excess risk irrespective of APOE polymorphism and gender. CONCLUSION: Genetic variation in the brain aromatase gene may modify the risk for AD.
Adult↗
Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients.
OBJECTIVES: Neprilysin (NEP) is an amyloid beta-peptide (Abeta) degrading enzyme expressed in the brain, and accumulation of Abeta is the neuropathological hallmark in Alzheimer's disease (AD). In this study we investigated whether polymorphisms in the NEP gene have an effect on the risk for AD. METHODS: The frequencies of seven single nucleotide polymorphisms (SNPs) and apolipoprotein E (APOE) were assessed in 390 AD patients and 468 cognitively healthy controls. Genotypes of the study groups were compared using binary logistic regression analysis. Haplotype frequencies of the SNPs were estimated from genotype data. RESULTS: Two SNPs, rs989692 and rs3736187, had significantly different allelic and genotypic frequencies (uncorrected p = 0.01) between the AD and the control subjects and haplotype analysis showed significant association between AD and NEP polymorphisms. CONCLUSION: Taken together, these findings suggest that polymorphisms in the NEP gene increase risk for AD and support a potential role for NEP in AD.
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Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy.
BACKGROUND: We determined whether genetic variability in the gene encoding the bile salt export pump (BSEP) contributes to individual differences in susceptibility to the development of intrahepatic cholestasis of pregnancy (ICP). METHODS: The study involved 57 affected and 115 healthy control pregnant women who were genotyped for two single nucleotide polymorphisms (SNPs) in the BSEP gene. Chi-square analysis was used to assess genotype and allele frequency differences between the cholestatic and control groups. In addition, single locus analysis was expanded to pair of loci haplotype analysis to examine the estimated haplotype frequencies of the two SNPs, of unknown phase, among the cholestatic and control groups. Estimated haplotype frequencies were assessed using the maximum-likelihood method, employing an expectation-maximization (EM) algorithm. RESULTS: The genotype and allele frequency distribution of the two intragenic SNPs in the ICP and control groups revealed significant evidence of association with the exon 28 SNP (P=0.04 and P=0.02, respectively). In addition, a borderline allele association was noted with the intron 19 SNP (P=0.08). Although the overall distribution of estimated haplotypes of intron 19 and exon 28 SNPs did not differ between the ICP and control groups, the most common haplotype, A-G, was significantly overrepresented in the ICP group (P=0.02), at an odds ratio of 1.73 (95% CI: 1.08-2.74). CONCLUSIONS: The use of two intragenic SNPs in both single locus and haplotype analyses of association suggests that the BSEP gene is a susceptibility gene in intrahepatic cholestasis of pregnancy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome.
BACKGROUND: In view of the strong evidence implicating peroxisome proliferator-activated receptor-gamma (PPARgamma) in adiposity and insulin resistance a study was carried out to investigate PPARgamma genotype frequencies in women with polycystic ovary syndrome (PCOS) and to elucidate its role in the pathogenesis of the syndrome. METHODS: The study involved 135 women with PCOS and 115 healthy control women who were genotyped for a known functional variant of the PPARgamma gene using single strand conformation polymorphism (SSCP) analysis. RESULTS: A significantly different allele distribution of the Pro12 Ala polymorphism of the PPARgamma gene was observed between the two groups, with the frequency of the variant Ala isoform being significantly reduced in the PCOS group (12.6%) when compared with the control group (19.1%) (P = 0.045), at an odds ratio of 0.609 (95% confidence interval: 0.374-0.991). The genotype distributions of the Pro12 Ala polymorphism in the PCOS and control groups were different with borderline significance (P = 0.051). CONCLUSIONS: Our data support a role for PPARgamma gene polymorphism in the pathogenesis of PCOS, the presence of the Ala isoform being protective against the development of PCOS.
Alleles↗
Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease.
Seladin-1 is a gene recently shown to be down-regulated in brain regions selectively degenerated in Alzheimer's disease. The sequence of seladin-1 shares similarities with flavin-adenine-dinucleotide-dependent oxidoreductases and it has been found to protect cells from apoptotic cell death. In this work, we show that the transcription of seladin-1 is selectively down-regulated in the brain areas affected in Alzheimer's disease. The down-regulation in seladin-1 transcription was associated with hyperphosphorylated tau seen as linkage to immunohistochemically detected paired helical filament tau, neuritic plaques and neurofibrillary tangles. In contrast, no association was found between seladin-1 transcription and beta-amyloid deposition when analyzing human samples or tissue from transgenic animals. Furthermore, the relative transcription of seladin-1 was found to fluctuate during aging in the transgenic mouse model of Alzheimer's disease. The fluctuation was enhanced by Alzheimer's disease causing mutations in presenilin-1 and amyloid precursor protein genes. Finally, seladin-1 transcription was found to be up-regulated in mouse N2a cells induced to undergo apoptosis with okadaic acid. The results presented here indicate that seladin-1 transcription is selectively down-regulated in brain regions vulnerable to Alzheimer's disease and this down-regulation is associated with the hyperphosphorylation of tau protein.
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Genome-wide linkage disequilibrium mapping of late-onset Alzheimer's disease in Finland.
BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
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An association between a subset of Finnish late-onset Alzheimer's disease and alpha2-macroglobulin.
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Age of Onset↗
The load and distribution of beta-amyloid in brain tissue of patients with Alzheimer's disease.
Recent findings have underlined the significance of beta-amyloid protein (betaA4) in the etiology of Alzheimer's disease (AD). In 60 patients with AD, the amount of betaA4 deposition, estimated applying immunohistochemical techniques, was shown to be significantly influenced by apolipoprotein E (ApoE) genotype (epsilon4/epsilon4 > epsilon4/x > x/x), by the age at onset (presenile > senile), by the age at death (younger > older patients) and by the duration of the disease (long > short). Morphometric analysis revealed that the betaA4 load was highest in the superficial layer of the cortex and a significant influence on the vertical distribution was seen in females but not in males, in familial but not in sporadic cases and in senile but not in presenile cases. Our findings indicate that not only the load but also the vertical distribution of betaA4 within cortex is influenced by risk factors such as ApoE genotype and gender.
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Maternal susceptibility locus for obstetric cholestasis maps to chromosome region 2p13 in Finnish patients.
BACKGROUND: Obstetric cholestasis, attributed to maternal hypersensitivity to estrogens, is a pregnancy-specific disorder characterized by pruritus and biochemical cholestasis in the second or third trimester of pregnancy. The pathophysiology of the disorder is incompletely understood, but the familial nature of the disease has long been recognized. Carriership of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency has been reported to be associated with an increased risk of obstetric cholestasis and the gene is located in the p23 region of chromosome 2. METHODS: On the basis of this information, we conducted population-based linkage disequilibrium (LD) screening to find potential cholestasis-associated loci on chromosome 2. The study was carried out in 47 unrelated control women and in 45 cholestatic women, eight of whom had a positive family history. RESULTS: During initial screening with chromosome 2-specific microsatellite markers, the tetranucleotide marker D2S1394 was found to be in LD in the 2p13 region. Screening this region with additional microsatellite markers revealed that the adjacent marker D2S1374 was also significantly associated with obstetric cholestasis, whereas no association was found with the markers located in the vicinity of the hydroxyacyl-CoA dehyrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit (HADHA) gene. CONCLUSIONS: Collectively, these data suggest that there may be a novel obstetric cholestasis-associated gene located in the vicinity of the 2p13 LD region.
3-Hydroxyacyl CoA Dehydrogenases↗
Apolipoprotein E alleles in women with pre-eclampsia.
AIMS: To investigate the frequency of three apolipoprotein E (apoE) alleles among women with pre-eclampsia. METHODS: The presence of the three most common apoE alleles (epsilon 2, epsilon 3, epsilon 4) was determined by polymerase chain reaction-restriction fragment length polymorphism in two groups of women: healthy pregnant women (n = 91) and pregnant women with a diagnosis of pre-eclampsia (n = 133). In addition, the frequencies of the alleles in the general population in this area are presented for comparison. RESULTS: The frequency of the apo epsilon 4 allele was 18.4% among women with pre-eclampsia and 18.7% among healthy pregnant women (Fisher's exact test; p = 0.941), which is close to the rate in the general population in this area (19%). None of the apolipoprotein E genotypes was significantly over-represented, and homozygous genotype epsilon 4 was not associated with more severe clinical disease than were the other genotypes. CONCLUSION: The observed profiles of allele and genotype frequencies confirm an equilibrium state between apoE polymorphism and pre-eclampsia and suggest that apoE does not play a major role in the development of pre-eclampsia.
Adult↗
MPO and APOEepsilon4 polymorphisms interact to increase risk for AD in Finnish males.
BACKGROUND: Myeloperoxidase (MPO) is present in senile plaques and surrounding reactive microglia, but not in normal brain parenchyma. MPO in plaques is highest in APOE epsilon4 carriers, suggesting a functional interaction. An MPO promoter polymorphism (-463G/A) linked to increased MPO expression has been associated with increased risk of AD. METHODS: To further define the possible interaction of MPO and APOE epsilon4, we examined 127 patients with AD and 174 controls from a genetically homogeneous Finnish population. RESULTS: A significantly higher percentage of male patients with AD carried the MPO A and APOE epsilon4 alleles relative to men carrying neither allele (p < 0.001; OR, 11.4; 95% CI, 3.6 to 6.7). Male APOE epsilon4 carriers lacking the MPO A allele had an OR of 3.0 (p = 0.01; 95% CI, 1.3 to 6.9), indicating that MPO A enhances AD risk by 3.8-fold. Age at onset was lower in men carrying the MPO A and APOE epsilon4 alleles (Kaplan-Meier survival analysis; p = 0.01). Also, the MPO AA genotype was associated with selective mortality in men, but not in women. AA genotypes were absent from 159 male patients with AD and controls, representing the expected 5% to 6% in women and male controls younger than age 20. The -463A creates an estrogen receptor binding site that may contribute to these gender differences. CONCLUSIONS: MPO A and APOE epsilon4 alleles interact to increase the risk of AD in men but not in women in this Finnish cohort.
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The leucine (7)-to-proline (7) polymorphism in the signal peptide of neuropeptide Y is not associated with Alzheimer's disease or the link apolipoprotein E.
Both apolipoprotein E varepsilon4 allele (APOE varepsilon4) and neuropeptide Y (NPY) Pro(7)-variant have been reported to be associated with higher serum levels of total and LDL cholesterol. Since APOE varepsilon4 allele is also a major risk factor for the development of Alzheimer's disease (AD) and the genetic polymorphism of NPY has not previously been studied in dementing disorders, we have examined whether a novel polymorphism in a signal peptide of NPY gene is associated with AD alone or in combination with APOE varepsilon4. A total of 125 sporadic AD cases and 110 control individuals from Finland were genotyped for APOE and NPY genes using the polymerase chain reaction and restriction enzyme analysis. The APOE varepsilon4 allele frequency was significantly increased in the AD group compared with controls as expected. Instead, no significant differences were found between sporadic AD patients and controls either in the NPY genotype or allele frequencies or in combination with the APOE varepsilon4 allele. We conclude that APOE varepsilon4 allele represents a strong predictor of risk for AD.
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Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?
Nearly all of the presenilin-1 (PSEN-1) mutations are missense mutations leading to Alzheimer's disease (AD). The role of the mutation E318G (a substitution of glutamic acid to glycine) in the PSEN-1 is controversial. It has been found both in AD patients and in non-demented control individuals. Using the polymerase chain reaction and the restriction fragment length polymorphism method, we screened for E318G mutation in a total of 16 familial (FAD) cases, in 64 sporadic neuropathologically confirmed AD cases and in 270 non-demented controls including 35 neuropathologically confirmed individuals. We detected the E318G mutation in four FAD cases, seven sporadic AD cases and 10 control individuals with highly varying onset-ages. Odds ratios for carrying the mutation were 7.6 and 3 in FAD and sporadic AD cases, respectively. Our results suggest that this mutation could be a risk factor in the Finnish FAD and sporadic AD population. It may be in linkage disequilibrium with a pathogenic change somewhere else in the PSEN-1 gene or in close proximity to the PSEN-1 gene.
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DNA fragmentation, gliosis and histological hallmarks of Alzheimer's disease.
The extent of DNA fragmentation analysed using the TUNEL technique was evaluated in post-mortem human brain tissue. Twenty-four patients with clinical and histopathological diagnosis of Alzheimer's disease (AD) and a short post-mortem delay were analysed. We report an increase in the count of TUNEL-labelled cells as the pathology of AD intensifies. Our results point out a significant correlation between neurofibrillary tangle and senile/neuritic plaque score and TUNEL-labelled cells. Patients with two copies of apolipoprotein (Apo) Eepsilon4 allele had highest number of histopathological hallmarks lesions of AD, whereas the ApoE genotype did not significantly influence the density of TUNEL-positive cells. No significant correlation was found between beta-amyloid protein load and TUNEL-labelled cells. There was no relationship between the age at death, age at onset, extent of astrogliosis or microgliosis and TUNEL-labelled cells in our material.
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Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?
Mutations in the presenilin-1 (PS-1) gene have been shown to cause early onset Alzheimer's disease (EOAD) in an autosomal dominant manner. We have identified a novel 4.6-kb genomic deletion in the PS-1 gene in a Finnish EOAD family, which leads to an inframe exclusion of exon9 (delta9) from the mRNA transcript. This germline mutation results in a similar alteration in mRNA level as previously described with the variant AD and the delta9 splice-site mutations. In this present EOAD family, the clinical and neuropathological phenotype of patients are those of the typical AD without indications of spastic paraparesis or 'cotton wool' plaques, which are the hallmarks of the variant AD. A sequence analysis of the deletion crossover site of the mutant and corresponding wild type regions revealed complete homology with the recombigenic 26 bp Alu core sequence at intron 8. In addition, a segment at the intron 9 breakpoint displayed homology with the core sequence, but comparison of the 5' and 3' breakpoint sequences did not reveal significant identity favouring involvement of Alu core sequence-stimulated non-homologous recombination rather than Alu-mediated homologous pairing of the fragments. This study shows that large genomic rearrangements can affect the EOAD gene PS-1 through a mechanism, which may involve Alu core sequence-stimulated recombination.
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