Miwa Kenji, Inazu Akihiro, Kobayashi Junji, Higashikata Toshinori, Nohara Atsushi, Kawashiri Masaaki, Katsuda Shoji, Takata Mutsuko, Koizumi Junji, Mabuchi Hiroshi
Molecular Genetics of Cardiovascular Disorders, Division of Cardiology, Graduate School of Medical Science, Kanazawa University, Japan.
Clin Sci (Lond). 2005 Aug;109(2):183-8. doi: 10.1042/CS20050030.
The ratio of serum plant sterols to cholesterol is positively correlated with the fractional cholesterol absorption, whereas serum precursors of cholesterol synthesis are positively correlated with cholesterol synthesis. Recently, two ABC (ATP-binding cassette) transporters, ABCG5 and ABCG8, have been described as playing an important role in the absorption and excretion of sterols. In the present study, we tested the hypothesis that genetic variation in ABCG5/ABCG8 influences the levels of serum plant sterol (sitosterol) and cholesterol precursor (lathosterol) in Japanese primary hypercholesterolaemic patients (n = 100). We identified a novel mutation [859T/C (C287R)] and a novel polymorphism [1285A/G (M429V)] at the ABCG5/ABCG8 loci, as well as four polymorphisms reported previously [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1895C/T (A632V)]. In carriers of the novel M429V variant, the serum level of sitosterol and the sitosterol/cholesterol ratio were significantly higher than those in non-carriers (3.64 compared with 2.56 microg/ml, and 1.45 microg/mg compared with 1.00 microg/mg respectively; P < 0.01 for both), and serum lathosterol tended to be lower (1.95 microg/ml compared with 3.03 microg/ml; P = 0.08), whereas no significant difference was observed in other lipid profiles. These four polymorphisms (1810C/G, 161G/A, 1199C/A and 1285A/G) generated six haplotypes, and the C/G/C/G haplotype was significantly associated with a higher sitosterol level and sitosterol/cholesterol ratio compared with the other five haplotypes (P < 0.05 for both). We conclude that, in 8% of patients with hypercholesterolaemia, the novel ABCG8 M429V variant was associated with higher cholesterol absorption efficiency. Future studies should investigate whether these findings have implications for the optimal cholesterol-lowering drug treatment in hypercholesterolaemic patients.
血清植物甾醇与胆固醇的比值与胆固醇吸收分数呈正相关，而胆固醇合成的血清前体与胆固醇合成呈正相关。最近，两种ABC（ATP结合盒）转运蛋白ABCG5和ABCG8被描述为在甾醇的吸收和排泄中起重要作用。在本研究中，我们检验了以下假设：ABCG5/ABCG8基因变异会影响日本原发性高胆固醇血症患者（n = 100）的血清植物甾醇（谷甾醇）和胆固醇前体（羊毛甾醇）水平。我们在ABCG5/ABCG8基因座上鉴定出一个新的突变[859T/C（C287R）]和一个新的多态性[1285A/G（M429V）]，以及先前报道的四个多态性[1810C/G（Q604E）、161G/A（C54Y）、1199C/A（T400K）和1895C/T（A632V）]。在新的M429V变异携带者中，谷甾醇的血清水平和谷甾醇/胆固醇比值显著高于非携带者（分别为3.64与2.56μg/ml，以及1.45μg/mg与1.00μg/mg；两者P均<0.01），血清羊毛甾醇倾向于较低（1.95μg/ml与3.03μg/ml；P = 0.08），而在其他血脂谱中未观察到显著差异。这四个多态性（1810C/G、161G/A、1199C/A和1285A/G）产生了六种单倍型，与其他五种单倍型相比，C/G/C/G单倍型与较高的谷甾醇水平和谷甾醇/胆固醇比值显著相关（两者P<0.05）。我们得出结论，在8%的高胆固醇醇醇胆固醇血症患者中，新的ABCG8 M429V变异与较高的胆固醇吸收效率相关。未来的研究应调查这些发现是否对高胆固醇血症患者的最佳降胆固醇药物治疗有影响。
