Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia
Identification of TNFRSF1B as a novel modifier gene in familial combined hyperlipidemia
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DOI：
10.1093/hmg/9.14.2067
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发表时间：
2000-09-01
影响因子：
3.5
通讯作者：
de Bruin, TWA
中科院分区：
文献类型：
--
作者：
Geurts, JMW;Janssen, RGJH;de Bruin, TWA
家族性混合性高脂血症（FCHL）是人类最常见的遗传性高脂血症，在一般人群中的发生率为+/-1%，在心肌梗死幸存者中的发生率为10%。在18个荷兰FCHL家庭的基因组扫描结果在几个位点的连锁证据的鉴定。其中一个区域1 p36，2包含TNFRSF 1B，它编码一种肿瘤坏死因子受体。内含子4多态性CA重复用于确认与FCHL的连锁。使用79个独立siB对的线性回归分析显示与定量FCHL判别函数相关（P = 0.032），与载脂蛋白B水平相关（P = 0.064）。此外，在一项病例对照研究中，由于40名无血缘关系的FCHL患者和48名无血缘关系的健康配偶对照的总体CA重复基因型分布存在显著差异，因此证明了相关性FCHL患者中等位基因CA 271纯合子显著增加（P = 0.029对73名FCHL家系成员的第6外显子进行了突变分析，结果显示存在一个单核苷酸多态性（SNP），即编码蛋氨酸（196 M）和精氨酸（196 R）的两个等位基因，在CA 267、CA 271和CA 273之间存在完全连锁不平衡。在85名高脂血症FCHL受试者中，证明了可溶性TNFRSF 1B血浆浓度与CA 271 - 196 M单倍型之间存在关联。总之，发现TNFRSF 1B与FCHL的易感性相关。我们的数据表明，一种与等位基因196 M和CA 271相关的迄今为止未知的疾病相关突变在FCHL的病理生理学中发挥着作用。
Familial combined hyperlipidemia (FCHL) is the most commonly inherited hyperlipidemia in man, with a frequency of +/-1% in the general population and similar to 10% in myocardial infarction survivors. A genomic scan in 18 Dutch FCHL families resulted in the identification of several loci with evidence for linkage. One of these regions, 1p36,2, contains TNFRSF1B which encodes one of the tumor necrosis factor receptors. An intron 4 polymorphic CA-repeat was used to confirm linkage to FCHL. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function (P = 0,032), and, borderline, with apolipoprotein B levels (P = 0.064). Furthermore, in a case-control study, association was demonstrated since the overall CA-repeat genotype distribution was significantly different among 40 unrelated FCHL patients and 48 unrelated healthy spouse controls (P = 0.029), This difference was due to a significant increase in allele CA271 homozygotes in the FCHL patients (P = 0,019), Mutation analysis of exon 6 in 73 FCHL family members demonstrated the presence of a single nucleotide polymorphism with two alleles, coding for methionine (196M) and arginine (196R), Complete linkage disequilibrium between CA267, CA271 and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype, In conclusion, TNFRSF1B was found to be associated with susceptibility to FCHL, Our data suggest that an as yet unknown disease-associated mutation, linked to alleles 196M and CA271, plays a role in the pathophysiology of FCHL.