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

Abstract

SummaryBackgroundAdiposity amplifies the genetic risk of non‐alcoholic fatty liver disease (NAFLD).AimWe 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/m2), and genetic risk on liver fat and fibrosis.MethodsThis 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.ResultsOur sample included 2478 participants (54% women) with mean age and BMI of 40 (±8.5) years and 26.5(±5.1) kg/m2, 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).ConclusionOverweight‐years is strongly associated with NAFLD and clinically significant fibrosis and combined with polygenic risk may assist in defining the trajectory of NAFLD.