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on February 1, 2007

Arteriosclerosis, Thrombosis, and Vascular Biology. 2007
Published online before print February 1, 2007, doi: 10.1161/01.ATV.0000258945.76141.8a
A more recent version of this article appeared on April 1, 2007
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Submitted on August 28, 2006
Accepted on January 6, 2007

High Frequency of a Retinoid X Receptor {gamma} 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 ; and 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.

* To whom correspondence should be addressed. 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{alpha}, PPAR{gamma}2, PPAR{delta}, FXR, LXR{alpha}, and RXR{gamma} 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{alpha} Asp140Asn and Gly395Glu, PPAR{gamma}2 Pro12Ala, RXR{gamma} Gly14Ser, and FXR -1g->t variants. Only RXR{gamma} 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{gamma} 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{gamma} Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXR{gamma} Gly14.

Conclusion--These findings suggest that RXR{gamma} contributes to the genetic background of FCHL.
Key words: apolipoproteins • gene mutations • lipoprotein lipase • familial combined hyperlipidemia • nuclear receptors




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