Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

Abstract

Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m² , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001).

Conclusions: Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).

Figure 1

Figure 1a–1b: The significant shared gene effects rG of hepatic steatosis and hepatic fibrosis with metabolic risk factors. Hepatic steatosis (Figure 1a) had significant shared gene effects rG with BMI, systolic blood pressure, diastolic blood pressure, HDL, triglycerides, glucose, HOMA-IR, insulin, and HbA1c. Hepatic fibrosis (Figure 1b) had significant shared gene effects rG with BMI, HDL, triglycerides, glucose, HOMA-IR, insulin, and HbA1c.

Figure 1

Figure 1a–1b: The significant shared gene effects rG of hepatic steatosis and hepatic fibrosis with metabolic risk factors. Hepatic steatosis (Figure 1a) had significant shared gene effects rG with BMI, systolic blood pressure, diastolic blood pressure, HDL, triglycerides, glucose, HOMA-IR, insulin, and HbA1c. Hepatic fibrosis (Figure 1b) had significant shared gene effects rG with BMI, HDL, triglycerides, glucose, HOMA-IR, insulin, and HbA1c.

Figure 2

Hepatic steatosis and fibrosis has a shared genetic determination rG of 0.756.

Figure 3

Representative MRI-PDFF and MRE of a pair of 60 year old male twins concordant for both NAFLD (MRI-PDFF ≥5%) and hepatic fibrosis (MRE >3 kPa). Hepatic steatosis and fibrosis have significant shared gene effects with one another at 0.756 (95% CI: 0.716, 1), p=2.54e-5. Hepatic steatosis also has significant shared gene effects with BMI, systolic blood pressure, diastolic blood pressure, HDL cholesterol, triglycerides, glucose, HOMA-IR, insulin, and hemoglobin A1c, and hepatic fibrosis has significant shared gene effects with BMI, HDL cholesterol, triglycerides, glucose, HOMA-IR, insulin, and hemoglobin A1c.