Genetic covariance between gamma-glutamyl transpeptidase and fatty liver risk factors: role of beta2-adrenergic receptor genetic variation in twins

Abstract

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.

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.

Figure 1. Heritability (h²) estimates of GGT and fatty liver risk factors shown in the present twin cohort

These h² estimates (± SEM) are similar to previously published studies, suggesting generalizability of findings from our cohort. GGT has substantial heritability, at 49±8%. Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; GGT, gamma-glutamyl transpeptidase; LDL, low-density lipoprotein..

Figure 2. Linkage equilibrium (LD) across the ADRB2 locus using Haploview

Darker block color denotes stronger pair-wise correlation among SNPs, within one major LD block.

Figure 3. Figure 3A. ADRB2 haplotype-1 (AGGCCGGGC) effect on GGT in age-/sex-adjusted models

Results demonstrate a significant association (p <0.024), suggesting that ADRB2 plays a role in regulation of GGT secretion. Figure 3B. ADRB2 haplotype-1 (AGGCCGGGC) increases both GGT and triglycerides in plasma. Results illustrate the pleiotropic effect of ADRB2 genetic variation on fatty liver risk factors.

Figure 3. Figure 3A. ADRB2 haplotype-1 (AGGCCGGGC) effect on GGT in age-/sex-adjusted models

Results demonstrate a significant association (p <0.024), suggesting that ADRB2 plays a role in regulation of GGT secretion. Figure 3B. ADRB2 haplotype-1 (AGGCCGGGC) increases both GGT and triglycerides in plasma. Results illustrate the pleiotropic effect of ADRB2 genetic variation on fatty liver risk factors.