title: Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study.
abstract: OBJECTIVE
  The minor T-allele of rs780094 in the glucokinase regulator gene (GCKR) associates with a number of metabolic traits including higher triglyceride levels and improved glycemic regulation in study populations of mostly European ancestry. Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we sought to replicate these findings, examine them in a large population-based sample of African American study participants, and to investigate independent associations with other metabolic traits in order to determine if variation in GKCR contributes to their observed clustering. In addition, we examined the association of rs780094 with incident diabetes, coronary heart disease (CHD), and stroke over up mean follow-up times of 8, 15, and 15 years, respectively.
  
  
  METHODS
  Race-stratified analyses were conducted among 10,929 white and 3,960 black participants aged 45-64 at baseline assuming an additive genetic model and using linear and logistic regression and Cox proportional hazards models.
  
  
  RESULTS
  Previous findings replicated among white participants in multivariable adjusted models: the T-allele of rs780094 was associated with lower fasting glucose (p = 10(-7)) and insulin levels (p = 10(-6)), lower insulin resistance (HOMA-IR, p = 10(-9)), less prevalent diabetes (p = 10(-6)), and higher CRP (p = 10(-8)), 2-h postprandial glucose (OGTT, p = 10(-6)), and triglyceride levels (p = 10(-31)). Moreover, the T-allele was independently associated with higher HDL cholesterol levels (p = 0.022), metabolic syndrome prevalence (p = 0.043), and lower beta-cell function measured as HOMA-B (p = 0.011). Among black participants, the T-allele was associated only with higher triglyceride levels (p = 0.004) and lower insulin levels (p = 0.002) and HOMA-IR (p = 0.013). Prospectively, the T-allele was associated with reduced incidence of diabetes (p = 10(-4)) among white participants, but not with incidence of CHD or stroke.
  
  
  CONCLUSIONS
  Our findings indicate rs780094 has independent associations with multiple metabolic traits as well as incident diabetes, but not incident CHD or stroke. The magnitude of association between the SNP and most traits was of lower magnitude among African American compared to white participants.
authors.affiliation: School of Biological Sciences, University of Nebraska at Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Bi
authors.forename: Wen Hong Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Ron C
authors.initials: RC
authors.lastname: Hoogeveen
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.forename: Brad C
authors.initials: BC
authors.lastname: Astor
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D050197:Atherosclerosis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human