Department of Clinical and Medical Therapy, Unit of Atherosclerosis, University of Rome La Sapienza, Italy.
Atherosclerosis. 2010 Nov;213(1):206-11. doi: 10.1016/j.atherosclerosis.2010.08.055. Epub 2010 Aug 19.
Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits.
Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed.
No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 ± 66.8 vs. 197.1 ± 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 ± 15.8 vs. 51.0 ± 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 ± 0.11 vs. 0.46 ± 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR).
These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoproteins.
家族性复合型高脂血症（FCHL）与脂肪酸代谢异常有关。脂肪甘油三酯脂肪酶（PNPLA2）在脂肪组织和肝脏中脂肪酸周转中发挥关键作用。本研究旨在评估选定的 PNPLA2 变体是否可能影响 FCHL 的易感性或其与脂质相关的特征。
根据先前与游离脂肪酸（FFA）和总甘油三酯（TG）水平降低相关的研究结果以及较高的频率（MAF>0.25），在 PNPLA2 基因内选择了 4 个 SNP（rs7925131、rs7942159、rs66460720 和非同义 P481L）。对 83 个家系的 214 名 FCHL 个体和 103 名对照进行了这些 SNP 的基因分型，并重建了相应的单倍型。
个体 SNP 与 FCHL 特征之间没有关联。然而，两种 PNPLA2 单倍型与较低的 FCHL 风险相关（Bonferroni 校正后 P<0.004）。与其他单倍型相比，这些单倍型与较低的 TG（118.9±66.8 与 197.1±114.7 mg/dl；P=0.001）和较高的 HDL-C（62.3±15.8 与 51.0±15.0 mg/dl；P<0.005）相关。在研究对象的亚组（n=63）中，保护性单倍型也与较低的 FFA 水平相关（0.33±0.11 与 0.46±0.18 mEq/L；P<0.05）。这些作用独立于年龄、BMI 和 HOMA（IR）。
这些数据表明，PNPLA2 内的变体可能调节 FCHL 特征的 TG 成分，从而将 PNPLA2 作为该脂质紊乱的修饰基因。它们还表明 PNPLA2 在富含甘油三酯的脂蛋白代谢中的潜在作用。
