| [ Summary ] |
The background and the prognosis of patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are very variable. The genetic background affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of NASH and NASH—derived hepatocellular carcinoma (NASH—HCC), is still unknown. We investigated the genetic background of 902 histologically proven NAFLD patients using genome—wide association (GWA) studies, which included 476 NASH and 58 NASH—HCC cases. Rs2896019 in PNPLA3, rs1260326 in GCKR, and rs4808199 in GATAD2A were significantly associated with NAFLD. We newly identified that rs17007417 in DYSF is associated with NASH—HCC. The risk for NAFLD showed a multiplicative increase with the accumulation of risk alleles in PNPLA3, GCKR, and GATAD2A for those carrying six risk alleles as compared to those without the risk alleles. The number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, or type 3 NAFLD patients, and the number in PNPLA3 and DYSF was much higher in NASH—HCC than in NASH.
NASH was genetically and clinically different from the other NAFLD subgroups. We established risk estimation models for NAFLD, NASH, and NASH—HCC using multiple genetic markers. These results will improve the accuracy of NAFLD diagnoses and treatment decisions. |