Eurlings Petra M H, van der Kallen Carla J H, Vermeulen Vicky M M-J, de Bruin Tjerk W A
Department of Internal Medicine, Laboratory of Molecular Metabolism and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Mol Genet Metab. 2003 Nov;80(3):296-301. doi: 10.1016/S1096-7192(03)00138-0.
Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder characterized by premature coronary artery disease, dyslipidemia, insulin resistance, and impaired adipose tissue free fatty acid (FFA) metabolism. Increased adipose tissue FFA flux towards the liver may, in part, contribute to reduced insulin sensitivity and hyperlipidemia in FCHL. It was the objective of the present study to evaluate the contribution of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene to FCHL traits related to adipocyte lipid metabolism, dyslipidemia, and insulin resistance. In a case-control panel consisting of 79 FCHL probands and 124 spouse controls, polymorphic marker D3S1259 and three intragenic PPARgamma variants, i.e., 161C > T, Pro12Ala, and Pro115Gln, were studied. The Pro115Gln variant was not found in any of the subjects. Allele frequencies of the 161C > T, Pro12Ala variants, and D3S1259 did not differ significantly between FCHL probands and spouses. In FCHL probands, individuals heterozygous or homozygous for the 161T allele had lower plasma concentrations of FFA (P < 0.05) and glycerol (P < 0.01). No significant associations were found in spouses. These findings identify PPARgamma as a quantitative trait locus for FFA and glycerol, against a background of insulin resistance for adipose tissue lipid metabolism, and therefore as a modifier gene in FCHL.
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，其特征为早发性冠状动脉疾病、血脂异常、胰岛素抵抗以及脂肪组织游离脂肪酸（FFA）代谢受损。脂肪组织中FFA向肝脏的通量增加可能部分导致了FCHL患者胰岛素敏感性降低和高脂血症。本研究的目的是评估过氧化物酶体增殖物激活受体γ（PPARγ）基因对与脂肪细胞脂质代谢、血脂异常和胰岛素抵抗相关的FCHL特征的影响。在一个由79名FCHL先证者和124名配偶对照组成的病例对照研究中，研究了多态性标记D3S1259和三个PPARγ基因内变体，即161C>T、Pro12Ala和Pro115Gln。在所有受试者中均未发现Pro115Gln变体。FCHL先证者和配偶之间，161C>T、Pro12Ala变体以及D3S1259的等位基因频率无显著差异。在FCHL先证者中，161T等位基因杂合或纯合的个体血浆FFA浓度较低（P<0.05），甘油浓度较低（P<0.01）。在配偶中未发现显著关联。这些发现表明，在脂肪组织脂质代谢存在胰岛素抵抗的背景下，PPARγ是FFA和甘油的数量性状位点，因此是FCHL中的一个修饰基因。
