ATP-binding cassette transporter G8 M429V polymorphism as a novel genetic marker of higher cholesterol absorption in hypercholesterolaemic Japanese subjects
ATP-binding cassette transporter G8 M429V polymorphism as a novel genetic marker of higher cholesterol absorption in hypercholesterolaemic Japanese subjects
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DOI：
10.1042/cs20050030
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发表时间：
2005-08-01
期刊：
影响因子：
6
通讯作者：
Mabuchi, H
中科院分区：
文献类型：
--
作者：
Miwa, K;Inazu, A;Mabuchi, H
血清植物类固醇/胆固醇比值与胆固醇吸收分数呈正相关，而血清胆固醇合成前体与胆固醇合成呈正相关。最近，ABCG5和ABCG8两个ABC(三磷酸腺苷结合盒)转运蛋白被认为在类固醇的吸收和排泄过程中起着重要作用。在本研究中，我们验证了ABCG5/ABCG8基因变异影响日本原发性高胆固醇血症患者(n=100)血清植物类固醇(谷甾醇)和胆固醇前体(类固醇)水平的假设。我们在ABCG5/ABCG8基因座发现了一个新的突变[859T/C(C287R)]和一个新的多态[1285A/G(M429V)]，以及先前报道的四个多态[1810C/G(Q604E)，161G/A(C54Y)，1199C/A(T400K)和1895C/T(A632V)]。新变异型M429V携带者的血清谷甾醇水平和谷甾醇/胆固醇比值显著高于非携带者(分别为3.64比2.56和1.45微克/毫克比1.00微克/毫克；P<；0.01)，血清谷甾醇有降低的趋势(1.95微克/毫升比3.03微克/毫升；P=0.08)，而其他血脂指标则无显著差异。这4个单倍型(1810C/G、161G/A、1199C/A和1285A/G)产生了6种单倍型，与其他5种单倍型相比，C/G/C/G单倍型与谷甾醇水平和谷甾醇/胆固醇比值显著相关(P<；0.05)。我们得出结论，在8%的高胆固醇血症患者中，新的ABCG8 M429V变异与更高的胆固醇吸收效率有关。未来的研究应该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。
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 mu g/ml, and 1.45 mu g/mg compared with 1.00 mu g/mg respectively; P < 0.01 for both), and serum lathosterol tended to be lower (1.95 mu g/ml compared with 3.03 mu g/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.