title: High frequency of a retinoid X receptor gamma gene variant in familial combined hyperlipidemia that associates with atherogenic dyslipidemia.
abstract: 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.
  
  
  RESULTS
  We screened all the coding regions of the PPARalpha, PPARgamma2, PPARdelta, FXR, LXRalpha, and RXRgamma 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 PPARalpha Asp140Asn and Gly395Glu, PPARgamma2 Pro12Ala, RXRgamma Gly14Ser, and FXR -1g->t variants. Only RXRgamma 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 RXRgamma 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, RXRgamma Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXRgamma Gly14.
  
  
  CONCLUSIONS
  These findings suggest that RXRgamma contributes to the genetic background of FCHL.
authors.affiliation: Department of Lipidology, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8641, Japan. a-nohara@med.kanazawa-u.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Mihoko
authors.initials: M
authors.lastname: Mizuno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Takata
authors.forename: Shoji
authors.initials: S
authors.lastname: Katsuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Miwa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Junji
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Junji
authors.initials: J
authors.lastname: Koizumi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008078:Cholesterol, LDL / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics*; D050171:Dyslipidemias / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000097:blood / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D047491:Retinoid X Receptor gamma / Q000235:genetics*; D014162:Transfection
chemical_list: D008078:Cholesterol, LDL; D008055:Lipids; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D047491:Retinoid X Receptor gamma; D008071:Lipoprotein Lipase