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Common Hepatic Nuclear Factor-4 Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

¹ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California
² Department of Molecular Biology and Genomic Medicine, Instituto de Investigaciones Biomédicas de la Universidad National Autónoma de Mexico, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico
³ Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico
⁴ Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

Address correspondence and reprint requests to Päivi Pajukanta, MD, PhD, Assistant Professor, UCLA, Department of Human Genetics, Gonda Neuroscience and Genetics Research Center, 695 Charles E. Young Dr. South, Los Angeles, CA 90095-7088. E-mail: ppajukanta{at}mednet.ucla.edu

Abbreviations: apo, apolipoprotein; AUC, area under the curve; CHD, coronary heart disease; FBAT, family-based association test; HBAT, haplotype-based association test; FCHL, familial combined hyperlipidemia; HNF-4, hepatic nuclear factor-4; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism; USF1, upstream transcription factor 1

Hepatic nuclear factor-4 (HNF-4), a transcription factor involved in the regulation of serum lipid and glucose levels, has recently been associated with type 2 diabetes. The HNF-4 gene (HNF4A) resides on chromosome 20q12-q13.1, which, in addition to type 2 diabetes, has also previously been linked to high triglycerides in Finnish familial combined hyperlipidemia (FCHL) families. FCHL, characterized by elevated levels of serum total cholesterol, triglycerides, or both, is a common dyslipidemia observed in up to 20% of patients with premature coronary heart disease. Considering the clear phenotypic overlap between type 2 diabetes and FCHL, both predisposing to high serum triglycerides and glucose intolerance, we tested this gene for association in dyslipidemic families originating from two distinct populations, Finnish and Mexican, and comprising 1,447 subjects. Our data show that common HNF4A variants and haplotypes are associated with elevated serum lipid levels and the metabolic syndrome (P = 0.008–0.04), as well as with elevated glucose parameters (P = 0.008–0.03), using family-based association analysis. Importantly, both Finnish and Mexican families shared two common lipid-associated HNF4A haplotypes (P = 0.005 for total cholesterol and 0.006 for triglycerides). In conclusion, we show for the first time that common HNF4A variants are associated with high serum lipid levels and the metabolic syndrome.

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