| 1. |
- Reynolds, Chandra A, et al.
(författare)
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A survey of ABCA1 sequence variation confirms association with dementia.
- 2009
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Ingår i: Human mutation. - : Hindawi Limited. - 1098-1004 .- 1059-7794. ; 30:9, s. 1348-54
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Tidskriftsartikel (refereegranskat)abstract
- We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.
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| 2. |
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| 3. |
- Blomqvist, Mia E-L, et al.
(författare)
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Towards compendia of negative genetic association studies: an example for Alzheimer disease.
- 2006
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Ingår i: Human genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 119:1-2, s. 29-37
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Tidskriftsartikel (refereegranskat)abstract
- Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004-April 2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset, and cerebrospinal fluid (CSF) beta-amyloid (Abeta) and CSF tau proteins). Within this set, only modest signals were present that, with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future meta-analyses aimed at resolving the involvement of genes in complex human traits.
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| 4. |
- Corder, Elizabeth H, et al.
(författare)
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Genetic susceptibility sets for Alzheimer's disease identified from diverse candidate loci.
- 2008
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Ingår i: Rejuvenation research. - : Mary Ann Liebert Inc. - 1549-1684 .- 1557-8577. ; 11:3, s. 667-79
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) has been demonstrated to be associated with gene variants of APOE, but numerous additional candidate loci exist with varying levels of statistical support. We defined susceptibility sets for AD based on information on 18 genetic loci on chromosome 10q (32 loci) and elsewhere (34 loci) and quantitative traits, including CSF tau and Abeta(42) levels. The 938 AD patients and 397 control subjects were enrolled in Scotland and Sweden. A fuzzy latent classification approach -- grade-of-membership analysis (GoM) -- was taken to identify risk sets. Individuals were automatically related to each set via GoM scores. Set I: unaffected + (downward arrow) CSF tau + (upward arrow) CSF Abeta(42) + multiple protective alleles. High intrinsic risk sets II-VI differed in onset age and relevant alleles: close resemblance (i.e., >75% aggregate membership) multiplied risk of AD >100-fold at ages 65 to 84. It is likely that AD has multiple determinants, including APOE polymorphism and gene variants located on chromosome 10q and elsewhere.
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| 5. |
- Hong, Mun-Gwan, et al.
(författare)
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Evidence that the gene encoding insulin degrading enzyme influences human lifespan.
- 2008
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 17:15, s. 2370-8
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Tidskriftsartikel (refereegranskat)abstract
- Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to be occurring only in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider clarifying the biological importance of these findings.
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| 6. |
- Johansson, Annica, 1969, et al.
(författare)
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Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease
- 2005
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 20:6, s. 367-374
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Tidskriftsartikel (refereegranskat)abstract
- We have recently reported that a polymorphism in the cell division cycle <i>(CDC2) </i>gene, designated Ex6 + 7I/D, is associated with Alzheimer’s disease (AD). The <i>CDC2</i> gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, <i>CDC2 </i>is a promising candidate susceptibility gene for AD. We investigated the possible effects of the <i>CDC2</i> polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. <i>CDC2</i> genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and β-amyloid<sub>(1–42)</sub> in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The <i>CDC2</i> Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F<sub>2, 626</sub> = 7.0, p = 0.001) and the homozygous <i>CDC2</i> Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13–2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.
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| 9. |
- Zetterberg, Madeleine, 1969, et al.
(författare)
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Methylenetetrahydrofolate reductase genetic polymorphisms in patients with cataract.
- 2005
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Ingår i: American journal of ophthalmology. - : Elsevier BV. - 0002-9394. ; 140:5, s. 932-4
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Hyperhomocysteinemia is commonly associated with polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. The level of homocysteine can be lowered by dietary intake of folate. A protective effect of folate supplementation has been reported against cataract. Here we investigate MTHFR polymorphisms in human cataract. DESIGN: Retrospective case-control association study. METHODS: Patients with nuclear (n = 77), cortical (n = 155), posterior subcapsular (n = 119), and mixed (n = 151) cataract, and 187 controls were analyzed for the MTHFR 677C-->T and 1298A-->C polymorphisms using minisequencing technique. RESULTS: The wild-type MTHFR 677CC/1298AA genotype was strongly overrepresented among cataract cases (P = .003). This effect was most pronounced in the mixed cataract group (P < .001). Hyperhomocysteinemia-associated genotypes had similar frequencies in cataract and control groups. CONCLUSIONS: The previously reported protective effect of folate against cataract is not due to overrepresentation of hyperhomocysteinemia-associated MTHFR genotypes. Instead, the strong predominance of wild-type MTHFR in cataract may suggest impaired DNA synthesis as a cataractogenic factor.
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