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- 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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| 2. |
- 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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