A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries
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...
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ftpubmed:oai:pubmedcentral.nih.gov:2409978 2023-05-15T16:50:57+02:00 A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries Palsdottir, Astridur Helgason, Agnar Palsson, Snaebjorn Bjornsson, Hans Tomas Bragason, Birkir Thor Gretarsdottir, Solveig Thorsteinsdottir, Unnur Olafsson, Elias Stefansson, Kari 2008-06 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409978 http://www.ncbi.nlm.nih.gov/pubmed/18566660 https://doi.org/10.1371/journal.pgen.1000099 en eng Public Library of Science http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409978 http://www.ncbi.nlm.nih.gov/pubmed/18566660 http://dx.doi.org/10.1371/journal.pgen.1000099 Palsdottir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. CC-BY Research Article Text 2008 ftpubmed https://doi.org/10.1371/journal.pgen.1000099 2013-09-01T23:28:03Z 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. Text Iceland PubMed Central (PMC) PLoS Genetics 4 6 e1000099 |
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Research Article Palsdottir, Astridur Helgason, Agnar Palsson, Snaebjorn Bjornsson, Hans Tomas Bragason, Birkir Thor Gretarsdottir, Solveig Thorsteinsdottir, Unnur Olafsson, Elias Stefansson, Kari A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
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Research Article |
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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. |
format |
Text |
author |
Palsdottir, Astridur Helgason, Agnar Palsson, Snaebjorn Bjornsson, Hans Tomas Bragason, Birkir Thor Gretarsdottir, Solveig Thorsteinsdottir, Unnur Olafsson, Elias Stefansson, Kari |
author_facet |
Palsdottir, Astridur Helgason, Agnar Palsson, Snaebjorn Bjornsson, Hans Tomas Bragason, Birkir Thor Gretarsdottir, Solveig Thorsteinsdottir, Unnur Olafsson, Elias Stefansson, Kari |
author_sort |
Palsdottir, Astridur |
title |
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
title_short |
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
title_full |
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
title_fullStr |
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
title_full_unstemmed |
A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries |
title_sort |
drastic reduction in the life span of cystatin c l68q carriers due to life-style changes during the last two centuries |
publisher |
Public Library of Science |
publishDate |
2008 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409978 http://www.ncbi.nlm.nih.gov/pubmed/18566660 https://doi.org/10.1371/journal.pgen.1000099 |
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Iceland |
genre_facet |
Iceland |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409978 http://www.ncbi.nlm.nih.gov/pubmed/18566660 http://dx.doi.org/10.1371/journal.pgen.1000099 |
op_rights |
Palsdottir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1371/journal.pgen.1000099 |
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PLoS Genetics |
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4 |
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6 |
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e1000099 |
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1766041061555175424 |