Abstract
The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67–2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25–1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23–1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84–4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63–0.67)]. Conclusions: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is frequently associated with metabolic syndrome, a broad range of pathologies including nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (NASH-HCC)
In the comparison between type 4 and NASH-HCC, 11 clinical traits showed significant differences. All of these 11 markers were associated with the severity of fibrosis, decline of liver function, or a higher age range in the NASH-HCC compared to the type 4 NASH patients
PNPLA3 is the strongest genetic determinant known for the development of NAFLD and NASH-HCC[6,12]
Summary
Nonalcoholic fatty liver disease (NAFLD) is frequently associated with metabolic syndrome, a broad range of pathologies including nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (NASH-HCC). NAFLD is classified into four subgroups based on its long-term histological progression. Type 1 (steatosis) and type 2 (steatonecrosis) are classified as NAFL, and type 3 (steatohepatitis) and type 4 (steatohepatitis with fibrosis) as NASH[1]. The prevalence of NAFLD varies widely across the world; for example, it is rare in Asian countries and more common in North America[2]. It was recently reported that the overall NASH prevalence among biopsied NAFLD patients is 59.1% [2]. NAFLD including NASH has a highly varied natural history. In a longitudinal study of 81 NASH and 27 NAFL patients with serial liver biopsies, 45 (42%) patients showed fibrosis progression, while 20 (18%) showed regression after the median follow-up period of 6.6 years[3]
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