Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers

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.

Clinical features of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without advanced fibrosis

“…Kawaguchi et al reported that dysferlin and patatin-like phospholipase domain containing 3 single nucleotide polymorphisms were critical for NAFLD-HCC. 26 A prospective study will clarify the best screening system for HCC among NAFLD patients.…”

Review article: the emerging role of genetics in precision medicine for patients with non‐alcoholic steatohepatitis

“…This variant is associated with increased susceptibility to NAFLD, NASH and NASH‐derived HCC (Table 1). 44,45 The minor allele frequency of GCKR P446L in the 1000 Genomes Project phase 3 combined population is 29% 46 . GCKR P446L interacts with PNPLA3 I148M in elevating susceptibility to NASH in people with both risk alleles 45 …”

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

“…19 However, this association could not be replicated in populations of other ethnicities. [20][21][22] More recently, a study that involved the analysis of exome-sequence data coupled to electronic health records of 46,455 patients taking part in a large collaborative study revealed a loss-of-function variation in hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene that confers protection against chronic liver injury and mitigates progressive NASH among European Americans. 23 From the histopathologic point of view, NAFLD refers to potentially progressive lesions ranging from isolated steatosis (NAFL) to NASH 1 as explained above.…”