title: Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations.
abstract: OBJECTIVE
  Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval.
  
  
  METHODS
  We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the approximately 417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval.
  
  
  RESULTS
  We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (P(meta) = 3 x 10(-56)) and glucose (P(meta) = 1 x 10(-13)) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 x 10(-5)). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r(2) = 0.93 with rs780094) as the strongest association signal in the region.
  
  
  CONCLUSIONS
  These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
authors.affiliation: Department of Clinical Sciences, University Hospital Malmö, Clinical Research Center, Lund University, Malmö, Sweden. marju.orho-melander@med.lu.se
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Pablo
authors.initials: P
authors.lastname: Perez-Martinez
authors.forename: Dolores
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authors.lastname: Corella
authors.forename: Charlotta
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authors.lastname: Roos
authors.forename: Ryan
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authors.lastname: Tewhey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Jennifer
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authors.lastname: Hall
authors.forename: Goncalo
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authors.lastname: Abecasis
authors.forename: E Shyong
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authors.lastname: Tai
authors.forename: Cullan
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authors.lastname: Welch
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Valeriya
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authors.lastname: Lyssenko
authors.forename: Eero
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authors.lastname: Lindholm
authors.forename: Richa
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authors.lastname: Saxena
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tucker
authors.forename: Thomas
authors.initials: T
authors.lastname: Hedner
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Bo
authors.initials: B
authors.lastname: Isomaa
authors.forename: Karl-Fredrik
authors.initials: KF
authors.lastname: Eriksson
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Björn
authors.initials: B
authors.lastname: Wahlstrand
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hughes
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Parnell
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.forename: Göran
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authors.lastname: Berglund
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Erkki
authors.initials: E
authors.lastname: Vartiainen
authors.forename: Pekka
authors.initials: P
authors.lastname: Jousilahti
authors.forename: Aki S
authors.initials: AS
authors.lastname: Havulinna
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Sekar
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authors.lastname: Kathiresan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism*; D005215:Fasting / Q000097:blood; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D014280:Triglycerides; D002097:C-Reactive Protein