TY - JOUR
T1 - High frequency of a retinoid X receptor gamma gene variant in familial combined hyperlipidemia that associates with atherogenic dyslipidemia
AU - Nohara, Atsushi
AU - Kawashiri, Masa-aki
AU - Claudel, Thierry
AU - Mizuno, Mihoko
AU - Tsuchida, Masayuki
AU - Takata, Mutsuko
AU - Katsuda, Shoji
AU - Miwa, Kenji
AU - Inazu, Akihiro
AU - Kuipers, Folkert
AU - Kobayashi, Junji
AU - Koizumi, Junji
AU - Yamagishi, Masakazu
AU - Mabuchi, Hiroshi
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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.
KW - apolipoproteins
KW - gene mutations
KW - lipoprotein lipase
KW - familial combined hyperlipidemia
KW - nuclear receptors
KW - UPSTREAM STIMULATORY FACTOR-1
KW - LIPOPROTEIN-LIPASE ACTIVITY
KW - CORONARY HEART-DISEASE
KW - HEPATIC TRIGLYCERIDE LIPASE
KW - ELEVATED LIPID-LEVELS
KW - HUMAN-SERUM
KW - COMBINED HYPERLIPOPROTEINEMIA
KW - TRANSCRIPTION FACTOR-1
KW - CHROMOSOME 1Q21-Q23
KW - METABOLIC SYNDROME
U2 - 10.1161/01.ATV.0000258945.76141.8a
DO - 10.1161/01.ATV.0000258945.76141.8a
M3 - Article
SN - 1079-5642
VL - 27
SP - 923
EP - 928
JO - Arteriosclerosis thrombosis and vascular biology
JF - Arteriosclerosis thrombosis and vascular biology
IS - 4
ER -