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

Abstract

Background— The transcription factor hepatocyte nuclear factor (HNF)-1α 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-1α gene ( HNF1A ) were recently associated with plasma C-reactive protein and γ-glutamyl transferase concentration in middle-aged to older European Americans (EA). Methods and Results— We assessed whether common variants of HNF1A are associated with C-reactive protein, γ-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu ( rs 1169288) and Ser486Asn ( rs 2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and γ-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein 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 Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA. Conclusions— Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.