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Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expr...

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Autores principales: Keildson, Sarah, Fadista, Joao, Ladenvall, Claes, Hedman, Åsa K., Elgzyri, Targ, Small, Kerrin S., Grundberg, Elin, Nica, Alexandra C., Glass, Daniel, Richards, J. Brent, Barrett, Amy, Nisbet, James, Zheng, Hou-Feng, Rönn, Tina, Ström, Kristoffer, Eriksson, Karl-Fredrik, Prokopenko, Inga, Spector, Timothy D., Dermitzakis, Emmanouil T., Deloukas, Panos, McCarthy, Mark I., Rung, Johan, Groop, Leif, Franks, Paul W., Lindgren, Cecilia M., Hansson, Ola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931395/
https://www.ncbi.nlm.nih.gov/pubmed/24306210
http://dx.doi.org/10.2337/db13-1301
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author Keildson, Sarah
Fadista, Joao
Ladenvall, Claes
Hedman, Åsa K.
Elgzyri, Targ
Small, Kerrin S.
Grundberg, Elin
Nica, Alexandra C.
Glass, Daniel
Richards, J. Brent
Barrett, Amy
Nisbet, James
Zheng, Hou-Feng
Rönn, Tina
Ström, Kristoffer
Eriksson, Karl-Fredrik
Prokopenko, Inga
Spector, Timothy D.
Dermitzakis, Emmanouil T.
Deloukas, Panos
McCarthy, Mark I.
Rung, Johan
Groop, Leif
Franks, Paul W.
Lindgren, Cecilia M.
Hansson, Ola
author_facet Keildson, Sarah
Fadista, Joao
Ladenvall, Claes
Hedman, Åsa K.
Elgzyri, Targ
Small, Kerrin S.
Grundberg, Elin
Nica, Alexandra C.
Glass, Daniel
Richards, J. Brent
Barrett, Amy
Nisbet, James
Zheng, Hou-Feng
Rönn, Tina
Ström, Kristoffer
Eriksson, Karl-Fredrik
Prokopenko, Inga
Spector, Timothy D.
Dermitzakis, Emmanouil T.
Deloukas, Panos
McCarthy, Mark I.
Rung, Johan
Groop, Leif
Franks, Paul W.
Lindgren, Cecilia M.
Hansson, Ola
author_sort Keildson, Sarah
collection PubMed
description Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(−5)) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(−4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(−6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(−3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.
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spelling pubmed-39313952015-03-01 Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity Keildson, Sarah Fadista, Joao Ladenvall, Claes Hedman, Åsa K. Elgzyri, Targ Small, Kerrin S. Grundberg, Elin Nica, Alexandra C. Glass, Daniel Richards, J. Brent Barrett, Amy Nisbet, James Zheng, Hou-Feng Rönn, Tina Ström, Kristoffer Eriksson, Karl-Fredrik Prokopenko, Inga Spector, Timothy D. Dermitzakis, Emmanouil T. Deloukas, Panos McCarthy, Mark I. Rung, Johan Groop, Leif Franks, Paul W. Lindgren, Cecilia M. Hansson, Ola Diabetes Genetics/Genomes/Proteomics/Metabolomics Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10(−5)) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10(−4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10(−6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r(2) = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10(−3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity. American Diabetes Association 2014-03 2014-02-13 /pmc/articles/PMC3931395/ /pubmed/24306210 http://dx.doi.org/10.2337/db13-1301 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Genetics/Genomes/Proteomics/Metabolomics
Keildson, Sarah
Fadista, Joao
Ladenvall, Claes
Hedman, Åsa K.
Elgzyri, Targ
Small, Kerrin S.
Grundberg, Elin
Nica, Alexandra C.
Glass, Daniel
Richards, J. Brent
Barrett, Amy
Nisbet, James
Zheng, Hou-Feng
Rönn, Tina
Ström, Kristoffer
Eriksson, Karl-Fredrik
Prokopenko, Inga
Spector, Timothy D.
Dermitzakis, Emmanouil T.
Deloukas, Panos
McCarthy, Mark I.
Rung, Johan
Groop, Leif
Franks, Paul W.
Lindgren, Cecilia M.
Hansson, Ola
Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title_full Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title_fullStr Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title_full_unstemmed Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title_short Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity
title_sort expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity
topic Genetics/Genomes/Proteomics/Metabolomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931395/
https://www.ncbi.nlm.nih.gov/pubmed/24306210
http://dx.doi.org/10.2337/db13-1301
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