Background-The transcription factor hepatocyte nuclear factor (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 and ␥-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, ␥-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 (nϭ2154) and African American (AA; nϭ2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and ␥-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. (Circ Cardiovasc Genet. 2009;2:244-254.)Key Words: atherosclerosis Ⅲ genetics Ⅲ C-reactive protein Ⅲ HNF-1 Ⅲ ␥-glutamyl transferase T he transcription factor hepatocyte nuclear factor (HNF)-1␣ is expressed in the liver, kidney, and endocrine pancreas and regulates a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. [1][2][3][4][5][6][7][8] Sequence
Clinical Perspective on p 254variants of the gene encoding HNF-1␣, HNF1A (also known as TCF1) have been associated with several distinct cardiovascular disease (CVD) risk factors and metabolic pheno- In several recent genome-wide analyses, common variants of the HNF1A region on chromosome 12 were associated with circulating levels of fibrinogen, 10 C-reactive protein (CRP), 11,12 and ␥-glutamyl transferase (GGT). 13 Whether HNF1A variants are associated with these or other atherosclerotic and metabolic phenotypes in independent community-based samples that include nonwhite populations is unknown. Inflammation and thrombosis biomarkers, such...