Association of CYP46 intron 2 polymorphism in Finnish Alzheimer's disease samples and a global scale summary.
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Biomedical subjects
A Mannermaa
Publications and source records attributed to A Mannermaa.
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.
Aged↗
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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Midlife income, occupation, APOE status, and dementia: a population-based study.
OBJECTIVE: To examine the relationship between socioeconomic factors and APOE carrier status on the development of dementia. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1449 (73%) subjects aged 65 to 79 years were re-examined in 1998. The diagnosis of dementia among the nonparticipants was derived from patient records of the local hospitals and primary health care clinics. RESULTS: Low income level at old age was related to dementia, but low income level at midlife was not a risk factor for dementia. Dementia was also associated with decreasing income level, from midlife to old age 21 years later, when dementia was diagnosed. A sedentary occupation (office, service, or intellectual work) was associated with a decreased risk for dementia among participants; however, when the nonparticipants were included in the analysis, the associations were no longer significant. Low educational level and the APOE epsilon4 allele independently increased the risk for dementia. CONCLUSIONS: Reduction in income level during follow-up and low income level at old age might be the consequence of a dementing process rather than being associated with risk evolution of dementia.
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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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Lack of association between C-850T polymorphism of the gene encoding tumor necrosis factor-alpha and polycystic ovary syndrome.
In the present study, we determined whether genetic variability in the gene encoding tumor necrosis factor-alpha (TNF-alpha) contributes to individual differences in susceptibility to the development of polycystic ovary syndrome (PCOS). The study involved 87 Caucasian Finnish women with PCOS and 115 healthy control women who were genotyped for the C-850T polymorphism in the TNF-alpha gene promoter. Analysis by chi(2) was used to assess genotype and allele frequency differences between PCOS women and controls. A similar genotype distribution for the C-850T polymorphism was observed in the two groups, with the frequency of the variant T allele being 8.6% in the PCOS group and 9.6% in the control group (p = 0.862). Accordingly, the profile of genotype frequencies was similar in the groups. The observed profiles of allele and genotype frequencies confirm an equilibrium state between C-850T polymorphism and PCOS and suggest that polymorphism of the TNF-alpha gene is unlikely to contribute to the risk of PCOS.
Alleles↗
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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Antenatal genetic screening for congenital nephrosis.
This study was undertaken to study the applicability of genetic antenatal screening for the Finnish type of congenital nephrosis (CNF), which is a recessive disorder leading to nephrotic syndrome from birth. At Kuopio University Hospital, a total of 1303 pregnant women were offered carrier screening for CNF at the time of first trimester nuchal fold translucency measurement when fetally derived alpha-fetoprotein is still produced by the yolk sac. Two mutations of the nephrin (NPHS 1) gene, accounting for approximately 95% of affected alleles, were tested by two PCR tests. Uptake of the gene test was 91.0% (n=1183). Altogether 38 female carriers were found; a population carrier frequency of 1 in 31. Their partners were tested and two of them were also found to be carriers. In these two pregnancies invasive prenatal diagnosis was offered and accepted, and the results indicated one carrier and one affected fetus. Carrier screening is an effective and well-accepted method for antenatal screening for fetal CNF. Direct mutation analysis involves markedly less invasive procedures compared with serum alpha-fetoprotein (AFP) screening, and the diagnosis was clear-cut. The results indicate that in single-gene disorders genetic testing is suitable for antenatal screening.
Alleles↗
Antenatal gene tests in low-risk pregnancies: molecular screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL) in Finland.
Approximately one in five subjects in Finland carries some gene defect associated with 30 diseases belonging to the Finnish disease heritage, and about one in 500 children born is affected. Almost all carriers, women and men, are unaware of their condition. Recent advances in molecular medicine have offered the possibility of population-based carrier screening for recessive disorders. We studied acceptance and attitudes to antenatal screening for aspartylglucosaminuria (AGU) and infantile neuronal ceroid lipofuscinosis (INCL). From January 1995 until December 1996 carrier tests were offered at Kuopio City Health Center, free of charge to all pregnant women attending maternity care units. Women found to be carriers of AGU (n = 47) or INCL (n = 14) underwent detailed genetic counseling, and their male partners were also offered the test. If both partners appeared to be carriers we offered prenatal testing (n = 1). No affected fetuses were detected. Attitudes towards the gene test were elicited by means of a questionnaire. Altogether 87% of pregnant women elected to undertake the gene tests. Antenatal screening for gene defects was feasible and well accepted, and it provided an effective way to find carriers of genetic diseases and to incorporate prenatal testing into this process.
Adult↗
An association between a subset of Finnish late-onset Alzheimer's disease and alpha2-macroglobulin.
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Age of Onset↗
Apolipoprotein E alleles in women with polycystic ovary syndrome.
OBJECTIVE: To investigate the frequency of apoE alleles among women with polycystic ovary syndrome. DESIGN: Retrospective case-control study. SETTING: University-based endocrinology/infertility clinic. PATIENT(S): Healthy fertile women (n = 91) and women with a diagnosis of polycystic ovary syndrome (n = 58). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The presence of the three most common apoE alleles (epsilon2, epsilon3, and epsilon4) determined by polymerase chain reaction-restriction fragment length polymorphism in the two groups and in the general population in our area. RESULT(S): The frequency of the apo epsilon4 allele was 17.2% among women with polycystic ovary syndrome and was 18.7% among healthy fertile women, which is close to the rate in the general population in our area (19%). None of the apoE genotypes (Fisher's exact test; P=.71) or alleles (P=.78) was significantly overrepresented, and the homozygous genotype epsilon4 was not associated with the clinical disease. CONCLUSION(S): The observed profiles of allele and genotype frequencies confirm the equilibrium state between apoE polymorphism and polycystic ovary syndrome and suggest that apoE does not play a major role in the development of hyperlipidemia in the group of women with polycystic ovary syndrome.
Alleles↗
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↗
Wide scope prenatal diagnosis at Kuopio University Hospital 1997-1998: integration of gene tests and fetal karyotyping.
OBJECTIVE: To investigate the applicability of carrier screening in women undergoing invasive prenatal diagnosis. DESIGN: Prospective study. SETTING: University-based clinic. PARTICIPANTS: Two hundred and fifty-six pregnant women. METHODS: Gene tests were offered for fragile X syndrome, aspartylglycosaminuria and infantile neuronal ceroid lipofuscinosis at the time of invasive prenatal testing. RESULTS: The overall uptake of the tests was 92%. Previously unrecognised carriership was found in 10 women: aspartylglycosaminuria (7); infantile neuronal ceroid lipofuscinosis (2) and fragile X (1). Fetal genotyping was carried out in one carrier of aspartylglycosaminuria whose partner was also a carrier, and in one woman who was found to have fragile X premutation. Both fetuses were unaffected. CONCLUSION: Carrier screening for single-gene disorders is feasible and well accepted among pregnant women undergoing invasive prenatal testing. The major benefit is that there is no need to consider extra invasive tests when carriership is detected. Incorporation of genetic testing into fetal karyotyping gives more security to future parents.
Cohort Studies↗
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↗
Increased risk of sensorineural hearing loss and migraine in patients with a rare mitochondrial DNA variant 4336A>G in tRNAGln.
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Adenosine Triphosphatases↗
The extent of linkage disequilibrium in four populations with distinct demographic histories.
The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.
Africa↗
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.
Age of Onset↗