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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2222.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

USF1 Contributes to High Serum Lipid Levels in Dutch FCHL Families and U.S. Whites With Coronary Artery Disease

Jenny C. Lee; Daphna Weissglas-Volkov; Mira Kyttälä; Janet S. Sinsheimer; Anne Jokiaho; Tjerk W.A. de Bruin; Aldons J. Lusis; Marie-Luise Brennan; Marleen M.J. van Greevenbroek; Carla J.H. van der Kallen; Stanley L. Hazen; Päivi Pajukanta

From the Department of Human Genetics, David Geffen School of Medicine at UCLA (J.C.L., D.W.-V., M.K., J.S.S, A.J., A.J.L., P.P), Departments of Biomathematics and Biostatistics (J.S.S.) and Departments of Medicine and Microbiology, Immunology, and Molecular Genetics (A.J.L.) at UCLA, Los Angeles, Calif; Department of Internal Medicine and the Cardiovascular Research Institute Maastricht (C.J.H.v.d.K., M.M.J.v.G., T.W.A.d.B.), Maastricht University, Maastricht, the Netherlands; Cleveland Clinic, Departments of Cardiovascular Medicine and Cell Biology, and Center for Cardiovascular Diagnostics & Prevention (M.B., S.L.H.), Cleveland, Ohio. Present address of T.W.A.d.B.: GlaxoSmithKline, Translational Medicine and Genetics, Research Triangle Park, NC.

Correspondence to Dr Päivi Pajukanta, Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda Building Rm. 6335B, 695 Charles Young Drive South, Los Angeles, CA 90095. E-mail ppajukanta{at}mednet.ucla.edu

Objective— Familial combined hyperlipidemia (FCHL) characterized by high serum total cholesterol and/or triglycerides (TGs) is a common dyslipidemia predisposing to coronary artery disease (CAD). Recently, the upstream transcription factor 1 (USF1) was linked and associated with FCHL and TGs in Finnish FCHL families. Here we examined the previously associated rs3737787 SNP in extended Dutch FCHL families (n=532) and in a cohort of US subjects who underwent diagnostic coronary angiography (n=1533).

Methods and Results— In males of the Dutch FCHL families, we observed significant sex-dependent associations between the common allele of rs3737787 and FCHL, TGs, and related metabolic traits (P=0.02 to 0.006). In the U.S. Whites, sex-dependent associations with TGs and related metabolic traits were observed for the common allele of rs3737787 in males (P=0.04 to 0.02) and rare allele in females (P=0.05 to 0.002). This intriguing relationship was further supported by the highly significant genotype x sex interactions observed for TGs in the Dutch and TGs and body mass index (BMI) in U.S. White subjects with CAD (P=0.0005 to 0.00004).

Conclusion— These data show that USF1 influences several cardiovascular risk factors in a sex-dependent manner in Dutch FCHL families and U.S. Whites with CAD. A significant interaction between sex and genotype was shown to affect TGs and BMI.

A variant of USF1 originally associated with FCHL in Finnish FCHL families was shown to be significantly associated with lipids and related metabolic traits in Dutch FCHL families and in a U.S. White cohort with CAD. Furthermore, a significant sex-genotype interaction was observed in both study samples.

Key Words: upstream transcription factor 1 • familial combined hyperlipidemia • coronary artery disease • association • lipids

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