Hepatic nuclear factor-4alpha (HNF-4alpha), a
transcription factor involved in the regulation of serum
lipid and
glucose levels, has recently been associated with
type 2 diabetes. The HNF-4alpha 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.