Genetic Covariance Between γ-Glutamyl Transpeptidase and Fatty Liver Risk Factors: Role of β₂-Adrenergic Receptor Genetic Variation in Twins

Background & Aims

Plasma levels of γ-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 β2-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.

Methods

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.

Results

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.

Conclusions

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.

Keywords: GGT, NAFLD, ADRB2, Metabolic Syndrome

Abbreviations used in this paper: ADRB2, β₂-adrenergic receptor, BChE, butyryl-cholinesterase, BMI, body mass index, GEE, generalized estimating equation, GGT, γ-glutamyl transpeptidase, h², heritability, HOMA, homeostasis model of insulin resistance, IR, insulin resistance, NAFLD, nonalcoholic fatty liver disease, SNP, single nucleotide polymorphism, ρ_E, rho-E (environmental covariance between traits), ρ_G, rho-G (genetic covariance between traits)