Eurlings Petra M H, van der Kallen Carla J H, Geurts Jan M W, Flavell David M, de Bruin Tjerk W A
Department of Internal Medicine, Laboratory of Molecular Metabolism and Endocrinology, Cardiovascular Research Institute Maastricht, University of Maastricht, PO Box 616, Maastricht, NL-6200 MD, The Netherlands.
Mol Genet Metab. 2002 Dec;77(4):274-81. doi: 10.1016/s1096-7192(02)00174-9.
Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder that is present in 10% of patients with premature coronary artery disease (CAD). It was the objective of the present study to evaluate the possible involvement of the PPARA locus in the pathophysiology of FCHL. Mutation detection analyses of the six coding PPARA exons resulted in the identification of four novel variants, [C/T] intron 3, S234G, [G/A] intron 5, and [C/A] 3(') UTR in three FCHL probands, whereas no novel variants were identified in spouses. In a case-control study, markers D22S275 and D22S928 were shown not to be associated with FCHL. However, D22S928, mapped within 1Mb of the PPARA gene, was shown to have a modifying effect on plasma apoCIII concentrations (P=0.011) and the combined hyperlipidemic FCHL phenotype (P=0.038). In addition two PPARA polymorphisms in intron 2 and 7 were studied, but these were not associated with FCHL. The frequency of the L162V variant was less in FCHL probands (1.98%) compared to that in spouses (4.84%). These results clearly demonstrate the genetically complex nature of FCHL and identify the PPARA gene as a modifier of the FCHL phenotype.
家族性混合性高脂血症（FCHL）是一种常见的遗传性脂质紊乱疾病，在10%的早发性冠状动脉疾病（CAD）患者中存在。本研究的目的是评估PPARA基因座在FCHL病理生理学中的可能作用。对PPARA的六个编码外显子进行突变检测分析，在三名FCHL先证者中鉴定出四个新的变异体，即内含子3的[C/T]、S234G、内含子5的[G/A]和3'非翻译区的[C/A]，而在配偶中未发现新的变异体。在一项病例对照研究中，标记物D22S275和D22S928显示与FCHL无关。然而，位于PPARA基因1Mb范围内的D22S928被证明对血浆载脂蛋白CIII浓度（P=0.011）和混合性高脂血症FCHL表型（P=0.038）有修饰作用。此外，还研究了内含子2和7中的两个PPARA多态性，但它们与FCHL无关。与配偶（4.84%）相比，FCHL先证者中L162V变异体的频率较低（1.98%）。这些结果清楚地证明了FCHL的遗传复杂性，并确定PPARA基因为FCHL表型的修饰基因。
