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Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans
The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential c...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Genetics Society of America
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174929/ https://www.ncbi.nlm.nih.gov/pubmed/25236446 http://dx.doi.org/10.1534/genetics.114.162982 |
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author | Tsaih, Shirng-Wern Holl, Katie Jia, Shuang Kaldunski, Mary Tschannen, Michael He, Hong Andrae, Jaime Wendt Li, Shun-Hua Stoddard, Alex Wiederhold, Andrew Parrington, John Ruas da Silva, Margarida Galione, Antony Meigs, James Hoffmann, Raymond G. Simpson, Pippa Jacob, Howard Hessner, Martin Solberg Woods, Leah C. |
author_facet | Tsaih, Shirng-Wern Holl, Katie Jia, Shuang Kaldunski, Mary Tschannen, Michael He, Hong Andrae, Jaime Wendt Li, Shun-Hua Stoddard, Alex Wiederhold, Andrew Parrington, John Ruas da Silva, Margarida Galione, Antony Meigs, James Hoffmann, Raymond G. Simpson, Pippa Jacob, Howard Hessner, Martin Solberg Woods, Leah C. |
author_sort | Tsaih, Shirng-Wern |
collection | PubMed |
description | The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci. |
format | Online Article Text |
id | pubmed-4174929 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Genetics Society of America |
record_format | MEDLINE/PubMed |
spelling | pubmed-41749292014-10-02 Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans Tsaih, Shirng-Wern Holl, Katie Jia, Shuang Kaldunski, Mary Tschannen, Michael He, Hong Andrae, Jaime Wendt Li, Shun-Hua Stoddard, Alex Wiederhold, Andrew Parrington, John Ruas da Silva, Margarida Galione, Antony Meigs, James Hoffmann, Raymond G. Simpson, Pippa Jacob, Howard Hessner, Martin Solberg Woods, Leah C. Genetics Multiparental Populations The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci. Genetics Society of America 2014-09 2014-09-01 /pmc/articles/PMC4174929/ /pubmed/25236446 http://dx.doi.org/10.1534/genetics.114.162982 Text en Copyright © 2014 by the Genetics Society of America Available freely online through the author-supported open access option. |
spellingShingle | Multiparental Populations Tsaih, Shirng-Wern Holl, Katie Jia, Shuang Kaldunski, Mary Tschannen, Michael He, Hong Andrae, Jaime Wendt Li, Shun-Hua Stoddard, Alex Wiederhold, Andrew Parrington, John Ruas da Silva, Margarida Galione, Antony Meigs, James Hoffmann, Raymond G. Simpson, Pippa Jacob, Howard Hessner, Martin Solberg Woods, Leah C. Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title | Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title_full | Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title_fullStr | Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title_full_unstemmed | Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title_short | Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans |
title_sort | identification of a novel gene for diabetic traits in rats, mice, and humans |
topic | Multiparental Populations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174929/ https://www.ncbi.nlm.nih.gov/pubmed/25236446 http://dx.doi.org/10.1534/genetics.114.162982 |
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