title: HNF1A G319S variant, active cigarette smoking and incident type 2 diabetes in Aboriginal Canadians: a population-based epidemiological study.
abstract: BACKGROUND
  In a recent report of large-scale association analysis, a type 2 diabetes susceptibility locus near HNF1A was identified in predominantly European descent populations. A population-specific G319S polymorphism in HNF1A was previously identified in Aboriginal Canadians who have a high prevalence of type 2 diabetes. We aimed to investigate the association of the HNF1A G319S polymorphism with incident type 2 diabetes and to assess whether clinical risk variables for type 2 diabetes influence the association in an Aboriginal population.
  
  
  METHODS
  Of 606 participants who were free of diabetes at baseline in 1993-1995, 540 (89.1%) participated in 10-year follow-up assessments in 2003-2005. Fasting glucose and a 75-g oral glucose tolerance test were obtained to determine incident type 2 diabetes. Participants were genotyped for the HNF1A G319S polymorphism. Interviewers administered questionnaires on smoking behavior.
  
  
  RESULTS
  The incidence rates of type 2 diabetes were 14.2% (55/388) in major allele homozygotes and 31.2% (29/93) in minor allele carriers (p < 0.001). The HNF1A G319S carrier status was associated with incident type 2 diabetes (odds ratio [OR] 3.78 [95% CI 2.13-6.69]) after adjustment for age, sex, hypertension, triglyceride, HDL cholesterol, and waist circumference. A statistical interaction was observed between HNF1A G319S and baseline active cigarette smoking on the development of type 2 diabetes with similar adjustment (p = 0.006). When participants were stratified by baseline smoking status, HNF1A G319S carriers who were active smokers had increased risk of developing diabetes (OR 6.91 [95% CI 3.38-14.12]), while the association was attenuated to non-significance among non-smokers (1.11 [0.40-3.08]).
  
  
  CONCLUSIONS
  The HNF1A G319S variant is associated with incident type 2 diabetes in Aboriginal Canadians. Furthermore, cigarette smoking appears to amplify incident diabetes risk in carriers of HNF1A G319S.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Sylvia H
authors.initials: SH
authors.lastname: Ley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Harris
authors.forename: Mary
authors.initials: M
authors.lastname: Mamakeesick
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Philip W
authors.initials: PW
authors.lastname: Connelly
authors.forename: Joel
authors.initials: J
authors.lastname: Gittelsohn
authors.forename: Ravi
authors.initials: R
authors.lastname: Retnakaran
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hanley
mesh_terms: D000293:Adolescent; D000328:Adult; D044467:American Indian or Alaska Native / Q000235:genetics* / Q000706:statistics & numerical data; D002170:Canada / Q000453:epidemiology; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005500:Follow-Up Studies; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D015994:Incidence; D008297:Male; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology* / Q000235:genetics*; D014280:Triglycerides / Q000097:blood / Q000235:genetics; D055105:Waist Circumference / Q000235:genetics; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D014280:Triglycerides