title: Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Keildson
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.forename: Targ
authors.initials: T
authors.lastname: Elgzyri
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Nica
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Ström
authors.forename: Karl-Fredrik
authors.initials: KF
authors.lastname: Eriksson
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000626:Aminopeptidases / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D025203:Phosphofructokinase-1, Muscle Type / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D025203:Phosphofructokinase-1, Muscle Type; D000626:Aminopeptidases; C503944:ERAP2 protein, human