Department of Medicine, University of California at San Diego, La Jolla, California, USA.
Gastroenterology. 2010 Sep;139(3):836-45, 845.e1. doi: 10.1053/j.gastro.2010.06.009. Epub 2010 Jun 9.
BACKGROUND & AIMS: Plasma levels of gamma-glutamyl transpeptidase (GGT) are associated with risk factors for nonalcoholic fatty liver disease (NAFLD), such as dyslipidemia, insulin resistance (IR), and hypertension. Limited data exist on whether there is genetic covariance between plasma levels of GGT and NAFLD risk factors. Variants of beta2-adrenergic receptor gene (ADRB2) have been associated with dyslipidemia, IR, and hypertension, but its effect on GGT secretion is not known. We estimated the heritability of GGT using a twin-study design and examined the genetic covariance between GGT levels, IR, hypertension, levels of low-density lipoproteins and triglycerides, and ADRB2 variants.
We studied phenotypes of 362 twins; the heritabilities of increased GGT activity and genetic covariance with NAFLD risk factors were estimated by variance-component methodology. ADRB2 genotype associations with plasma GGT activity were examined using generalized estimating equations to account for intra-twinship correlations.
GGT activity was heritable at 49% +/- 8% of the twin cohort and had significant covariance with IR; insulin, triglyceride, and uric acid levels; and diastolic blood pressure. In generalized estimating equation models, the most common haplotype of ADRB2 was significantly associated with plasma GGT activity. Five single nucleotide polymorphisms in ADRB2 were associated with levels of GGT; ADRB2 haplotypes displayed pleiotropic effects on GGT and triglyceride levels.
In a twin study, GGT shared genetic codetermination with traits of metabolic syndrome. The ADRB2 gene had pleiotropic effects on plasma levels of GGT and triglycerides, indicating linked pathways (eg, adrenergic) between genetic susceptibility to NAFLD and metabolic syndrome.
血浆γ-谷氨酰转肽酶（GGT）水平与非酒精性脂肪性肝病（NAFLD）的危险因素相关，如血脂异常、胰岛素抵抗（IR）和高血压。关于 GGT 水平与 NAFLD 危险因素之间是否存在遗传协方差，现有数据有限。β2-肾上腺素能受体基因（ADRB2）的变异与血脂异常、IR 和高血压有关，但它对 GGT 分泌的影响尚不清楚。我们使用双胞胎研究设计来估计 GGT 的遗传性，并检查 GGT 水平、IR、高血压、低密度脂蛋白和甘油三酯水平与 ADRB2 变异之间的遗传协方差。
我们研究了 362 对双胞胎的表型；通过方差分量法估计 GGT 活性增加的遗传率和与 NAFLD 危险因素的遗传协方差。使用广义估计方程检查 ADRB2 基因型与血浆 GGT 活性的关联，以考虑双胞胎内相关性。
GGT 活性在双胞胎队列中具有 49% +/- 8%的遗传性，与 IR 有显著的协方差；胰岛素、甘油三酯和尿酸水平；和舒张压。在广义估计方程模型中，ADRB2 最常见的单倍型与血浆 GGT 活性显著相关。ADRB2 中的 5 个单核苷酸多态性与 GGT 水平相关；ADRB2 单倍型对 GGT 和甘油三酯水平表现出多效性效应。
在一项双胞胎研究中，GGT 与代谢综合征的特征具有共同的遗传决定因素。ADRB2 基因对 GGT 和甘油三酯水平具有多效性效应，表明 NAFLD 和代谢综合征遗传易感性之间存在相关途径（如肾上腺素能途径）。
