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

Keildson, Sarah; Fadista, Joao LU ; Ladenvall, Claes LU ; Hedman, Asa K.; Elgzyri, Targ LU ; Small, Kerrin S.; Grundberg, Elin; Nica, Alexandra C.; Glass, Daniel and Richards, J. Brent, et al. (2014) In Diabetes 63(3). p.1154-1165
Abstract
sing 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... (More)
sing 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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
63
issue
3
pages
1154 - 1165
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000331614200035
  • scopus:84894499261
ISSN
1939-327X
DOI
10.2337/db13-1301
language
English
LU publication?
yes
id
0061bb8e-89ed-48a5-92c4-fb91ff97431b (old id 4470224)
date added to LUP
2014-07-01 07:39:44
date last changed
2017-10-22 04:12:37
@article{0061bb8e-89ed-48a5-92c4-fb91ff97431b,
  abstract     = {sing 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 &gt;7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] &lt;5%; P &lt; 1.96 × 10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment-insulin resistance, and BMI) (FDR &lt;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.},
  author       = {Keildson, Sarah and Fadista, Joao and Ladenvall, Claes and Hedman, Asa K. and Elgzyri, Targ and Small, Kerrin S. and Grundberg, Elin and Nica, Alexandra C. and Glass, Daniel and Richards, J. Brent and Barrett, Amy and Nisbet, James and Zheng, Hou-Feng and Rönn, Tina and Ström, Kristoffer and Eriksson, Karl-Fredrik and Prokopenko, Inga and Spector, Timothy D. and Dermitzakis, Emmanouil T. and Deloukas, Panos and McCarthy, Mark I. and Rung, Johan and Groop, Leif and Franks, Paul and Lindgren, Cecilia M. and Hansson, Ola},
  issn         = {1939-327X},
  language     = {eng},
  number       = {3},
  pages        = {1154--1165},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity},
  url          = {http://dx.doi.org/10.2337/db13-1301},
  volume       = {63},
  year         = {2014},
}