Published Online
on April 6, 2009

A more recent version of this article appeared on June 1, 2009

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Original Article

Common Coding Variants of the HNF1A Gene are Associated with Multiple Cardiovascular Risk Phenotypes in Community-Based Samples of Younger and Older European-American Adults: The Coronary Artery Risk Development in Young Adults Study and the Cardiovascular Health Study

Alexander P. Reiner^1,9; Myron D. Gross²; Christopher S. Carlson¹; Suzette J. Bielinski³; Leslie A. Lange⁴; Myriam Fornage⁵; Nancy S. Jenny⁶; Jeremy Walston⁷; Russell P. Tracy⁶; O.Dale Williams⁸; David R. JacobsJr² and Deborah A. Nickerson¹

¹ University of Washington, Seattle, WA;
² University of Minnesota, Minneapolis, MN;
³ Mayo Clinic, Rochester, MN;
⁴ University of North Carolina, Chapel Hill, NC;
⁵ University of Texas Health Science Center at Houston, Houston, TX;
⁶ University of Vermont College of Medicine, Burlington, VT;
⁷ Johns Hopkins University School of Medicine, Baltimore, MD;
⁸ University of Alabama at Birmingham, Birmingham, AL

⁹ E-mail: apreiner{at}u.washington.edu

Background—The transcription factor hepatocyte nuclear factor 1 (HNF-1) regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 gene (HNF1A) were recently associated with plasma C-reactive protein (CRP) and gamma-glutamyl transferase (GGT) concentration in middle-aged to older European-Americans (EA).

Methods and Results—We assessed whether common variants of HNF1A are associated with CRP, GGT, and other atherosclerotic and metabolic risk factors, in the large, population-based CARDIA study of healthy young European-American (EA; n=2,154) and African-American (AA; n=2,083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower CRP and GGT levels in EA. The same HNF1A coding variants were associated with higher LDL cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and CRP, fibrinogen, LDL cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in CARDIA and with incident coronary heart disease in CHS. The Ile27Leu and Ser486Asn variants were 3-fold less common than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA.

Conclusions—Common polymorphisms of HNF1A appear to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

Key Words: atherosclerosis • genetics • C-reacitve protein • HNF-1 • gamma glutamyl transferase