A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries

2.50
Hdl Handle:
http://hdl.handle.net/2336/30310
Title:
A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries
Authors:
Palsdottir, Astridur; Helgason, Agnar; Palsson, Snaebjorn; Bjornsson, Hans Tomas; Bragason, Birkir Thor; Gretarsdottir, Solveig; Thorsteinsdottir, Unnur; Olafsson, Elias; Stefansson, Kari
Citation:
PLoS Genet. 2008, 4(6):e1000099
Issue Date:
1-Jun-2008
Abstract:
Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.
Description:
To access full text version of this article. Please click on the hyperlink "View/Open" at the bottom of this page
Additional Links:
http://dx.doi.org/10.1371%2Fjournal.pgen.1000099

Full metadata record

DC FieldValue Language
dc.contributor.authorPalsdottir, Astridur-
dc.contributor.authorHelgason, Agnar-
dc.contributor.authorPalsson, Snaebjorn-
dc.contributor.authorBjornsson, Hans Tomas-
dc.contributor.authorBragason, Birkir Thor-
dc.contributor.authorGretarsdottir, Solveig-
dc.contributor.authorThorsteinsdottir, Unnur-
dc.contributor.authorOlafsson, Elias-
dc.contributor.authorStefansson, Kari-
dc.date.accessioned2008-06-23T13:34:17Z-
dc.date.available2008-06-23T13:34:17Z-
dc.date.issued2008-06-01-
dc.date.submitted2008-06-23-
dc.identifier.citationPLoS Genet. 2008, 4(6):e1000099en
dc.identifier.issn1553-7404-
dc.identifier.pmid18566660-
dc.identifier.doi10.1371/journal.pgen.1000099-
dc.identifier.urihttp://hdl.handle.net/2336/30310-
dc.descriptionTo access full text version of this article. Please click on the hyperlink "View/Open" at the bottom of this pageen
dc.description.abstractHereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.urlhttp://dx.doi.org/10.1371%2Fjournal.pgen.1000099en
dc.subject.meshPubMed - in processen
dc.titleA drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuriesen
dc.typeArticleen
dc.contributor.departmentInstitute for Experimental Pathology, University of Iceland, Keldur, Reykjavik, Iceland. astripal@hi.isen
dc.identifier.journalPLoS geneticsen

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