Dietary contributions in the genetic variation of liver fibrosis: a genome-wide association study of fibrosis-4 index in the liver fibrosis development

Background: The fibrosis-4 (FIB-4) index is a non-invasive method to assess the severity of liver fibrosis. The development of liver fibrosis is influenced by genetic predisposition and dietary factors. However, the modulating effect of dietary factors on the genetic susceptibility of liver fibrosis remains unclear. The study aims to investigate the role of dietary factors in modulating the genetic susceptibility of liver fibrosis.

Methods: Here, we conducted a genome-wide association study (GWAS) of FIB-4 index-directed liver fibrosis risk, adjusted with diet, lifestyle factors, and hepatitis serological markers. The high (N = 1,476) and low (N = 36,735) liver fibrosis risk groups were defined with a FIB-4 > 2.67 and < 1.3, respectively.

Results: The age-related FIB-4 variation showed subjects with a FIB-4 > 2.67 (3.8%), indicating high fibrosis risk, occurred predominantly among individuals above 60 years old. The multivariable analysis showed that tea intake is significantly associated with a reduced risk of liver fibrosis. The GWAS adjusted for sex, age, age², dietary factors (tea and coffee consumption, vegetarian preference), lifestyle (alcohol consumption, physical activity), hepatitis serological markers (anti-HCV, HBsAg, HBeAg), and the top ten principal components indicated 25 genome-wide significant signals (p < 5 × 10^{- 8}). Two variants (rs56293029 and rs9389269) were previously associated with the FIB-4 index in alcohol-related cirrhosis, while the 23 SNPs remaining were novel. The rs9399136 (HBS1L) is a protective variant, and rs9274407 (HLA-DQB1) is a risk variant, both contributing to liver fibrosis development. Our results showed that genetic factors play a major role in liver fibrosis, while dietary factors have minor effects on disease progression. Pathway analysis suggested the potential of immune response and hematopoietic systems function in the pathogenesis of liver disease.

Conclusions: The studies not only revealed the protective role of rs9399136 (HBS1L) and the risk effect of rs9274407 (HLA-DQB1) toward liver fibrosis in a Taiwanese population, but also demonstrated that individual consumption patterns, such as tea uptake, have a minor impact on liver fibrosis prevention. The pathway analysis from GWAS variants further indicated the importance of immune responses in the pathogenesis of liver fibrosis.