Genetic etiology of isolated low HDL syndrome - Incidence and heterogeneity of efflux defects
Genetic etiology of isolated low HDL syndrome - Incidence and heterogeneity of efflux defects
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DOI：
10.1161/atvbaha.106.137646
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发表时间：
2007-05-01
影响因子：
8.7
通讯作者：
Marcel, Yves L.
中科院分区：
文献类型：
--
作者：
Kiss, Robert S.;Kavaslar, Nihan;Marcel, Yves L.
目的-我们已经使用了一种多层次的方法来确定遗传和细胞贡献者的高密度脂蛋白（HDL）缺乏症在124人subjects.Methods和结果-我们重新测序4个候选基因的HDL调节和确定几个功能性非同义突变，包括2载脂蛋白A-I（APOA 1），4卵磷脂：胆固醇酰基转移酶（LCAT）1例，磷脂转移蛋白（PLTP）1例，ATP结合盒转运蛋白ABCA 1 7例，88%（110/124）的HDL缺乏受试者未进行基因诊断。使用来自124名低HDL受试者和48名对照受试者的胆固醇负载单核细胞衍生的巨噬细胞进行的胆固醇外排试验显示，33%（41/124）的低HDL受试者具有低外排，尽管这些受试者中的大多数（34/41）不是功能障碍性ABCA 1等位基因的携带者。相比之下，仅2%的对照受试者表现出低外排（1/48）。在3个家庭没有ABCA 1突变，外排缺陷被发现cosegregate与低HDL.Conclusions -外排缺陷是常见的低HDL综合征，但大多数HDL缺乏的受试者与细胞胆固醇外排缺陷不窝藏ABCA 1突变，这表明新的途径有助于这种表型。
Objective - We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects.Methods and Results - We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin: cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL.Conclusions - Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.