Longitudinal association between overweight years, polygenic risk and NAFLD, significant fibrosis and cirrhosis.

Background: Adiposity amplifies the genetic risk of non-alcoholic fatty liver disease (NAFLD).

Aim: We evaluated the association between overweight-years, a cumulative exposure based on the product of the duration and severity of excess body weight (body mass index (BMI) ≥ 25 kg/m ), and genetic risk on liver fat and fibrosis.

Methods: This is a longitudinal analysis derived from a prospective cohort of adults in the Framingham Heart Study who underwent genotyping and vibration-controlled-transient-elastography with controlled attenuation parameter. Univariable and multivariable linear and logistic regression analyses were used to assess the association between overweight-years and liver fat and fibrosis. The association between genetic variants of liver fat (PNPLA3, TM6SF2, GCKR) and fibrosis (PNPLA3, TM6SF2, HSD17B13) was also assessed using a polygenic risk score.

Results: Our sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m , respectively. The mean follow-up was 14(±0.9) years, and each participant underwent three study visits. The prevalence of NAFLD was 28.3% (n = 700), and 207 (8.4%) had clinically significant fibrosis. In age-, sex- and diabetes-adjusted multivariable analyses, overweight-years (per SD) had a strong association with NAFLD (aOR 3.53 [95% CI: 3.10-4.02], p < 0.001), clinically significant fibrosis (aOR 1.60 [95% CI: 1.40-1.84], p < 0.001) and cirrhosis (aOR 1.81 [95% CI: 1.38-2.37], p < 0.001). High-polygenic risk was significantly associated with liver fat and clinically significant fibrosis (p < 0.05).

Conclusion: Overweight-years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD.