title: GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study.
abstract: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes.
  
  
  
  We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects.
  
  
  
  The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele β=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele β=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01).
  
  
  
  We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tin
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Balakrishnan
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Human Genetics Center, University of Texas School of Public Health, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Hoogeveen
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.|Department of Medicine, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.|Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Young
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: W H L
authors.initials: WH
authors.lastname: Kao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001741:Black or African American; D000483:Alleles; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D019344:Lactic Acid / Q000097:blood*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054645:Protein Phosphatase 1 / Q000235:genetics*; D044465:White People
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin; C586823:PPP1R3B protein, human; D054645:Protein Phosphatase 1