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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:923.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

High Frequency of a Retinoid X Receptor Gene Variant in Familial Combined Hyperlipidemia That Associates With Atherogenic Dyslipidemia

Atsushi Nohara; Masa-aki Kawashiri; Thierry Claudel; Mihoko Mizuno; Masayuki Tsuchida; Mutsuko Takata; Shoji Katsuda; Kenji Miwa; Akihiro Inazu; Folkert Kuipers; Junji Kobayashi; Junji Koizumi; Masakazu Yamagishi; Hiroshi Mabuchi

From the Departments of Lipidology (A.N., M.M., J. Kobayashi, H.M.) and Cardiovascular Medicine (M.K., M. Tsuchida, M. Takata, S.K., K.M., M.Y.), Graduate School of Medical Science, Kanazawa University, Japan; Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics (T.C., F.K.), University Medical Center Groningen, Groningen, the Netherlands; School of Health Sciences, Faculty of Medicine (A.I.), and Department of General Medicine (J. Koizumi), Kanazawa University Hospital, Japan.

Correspondence to Atsushi Nohara, Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8641, Japan. E-mail a-nohara{at}med.kanazawa-u.ac.jp

Objective— The genetic background of familial combined hyperlipidemia (FCHL) has not been fully clarified. Because several nuclear receptors play pivotal roles in lipid metabolism, we tested the hypothesis that genetic variants of nuclear receptors contribute to FCHL.

Methods and Results— We screened all the coding regions of the PPAR, PPAR2, PPAR, FXR, LXR, and RXR genes in 180 hyperlipidemic patients including 60 FCHL probands. Clinical characteristics of the identified variants were evaluated in other 175 patients suspected of coronary disease. We identified PPAR Asp140Asn and Gly395Glu, PPAR2 Pro12Ala, RXR Gly14Ser, and FXR –1g–>t variants. Only RXR Ser14 was more frequent in FCHL (15%, P<0.05) than in other primary hyperlipidemia (4%) and in controls (5%). Among patients suspected of coronary disease, we identified 9 RXR Ser14 carriers, who showed increased triglycerides (1.62±0.82 versus 1.91±0.42 [mean±SD] mmol/L, P<0.05), decreased HDL-cholesterol (1.32±0.41 versus 1.04±0.26, P<0.05), and decreased post-heparin plasma lipoprotein lipase protein levels (222±85 versus 149±38 ng/mL, P<0.01). In vitro, RXR Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXR Gly14.

Conclusion— These findings suggest that RXR contributes to the genetic background of FCHL.

We investigated prevalence of genetic variants of several nuclear receptors in FCHL. We found a specific RXR variant to be significantly more frequent in FCHL and to be associated with atherogenic dyslipidemia and reduced lipoprotein lipase expression. We suggest a contribution of this RXR variant to FCHL.

Key Words: apolipoproteins • gene mutations • lipoprotein lipase • familial combined hyperlipidemia • nuclear receptors

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