Original ArticlePancreas, Biliary Tract, and LiverDevelopment and Validation of a Scoring System, Based on Genetic and Clinical Factors, to Determine Risk of Steatohepatitis in Asian Patients with Nonalcoholic Fatty Liver Disease
Section snippets
Patients and Assessment of Liver Histology
We constructed a prospective cohort from the ongoing Boramae NAFLD registry.7 Among the eligible study participants, only biopsy-proven NAFLD patients with sufficient clinical data for calculating scores were finally included in this study (N = 453) (Supplementary Methods). They were divided into cohort 1 (N = 302) and cohort 2 (N = 151) according to the period of enrollment. Cohort 1 consisted of individuals enrolled from February 2014 to March 2016 to build a model to determine patients’ risk
Characteristics of the Discovery and Replication Cohorts
In cohort 1 (n = 302) and cohort 2 (n = 151), 145 (48.0%) and 67 (44.4%) patients, respectively, were classified as NASH (P = .464) (Table 1). Cohort 2 showed significantly lower high-density lipoprotein cholesterol, higher AST and alanine aminotransferase, lower albumin, and higher HOMA-IR levels than cohort 1 (P = .019, .016, .038, .001, and < .001, respectively) (Table 1).
The genotypic distributions of PNPLA3 rs738409, TM6SF2 rs58542926, SREBF2 rs133291, MBOAT7-TMC4 rs641738, and HSD17B13
Conclusions
In the current study, we successfully developed a NASH-identifying polygenic risk scoring model incorporating 2 genetic risk variants, such as PNPLA3 rs738409 and TM6SF2 rs58542926, from our biopsy-proven NAFLD cohort and validated it using an independent replication dataset. Its AUROC for differentiating NASH from NAFL was 0.859 and 0.787 in the discovery and replication cohorts, respectively. In the replication cohort, the AUROC of the newly developed model (NASH PT score) was significantly
References (33)
- et al.
Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States
Gastroenterology
(2015) - et al.
Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study
Lancet
(2016) - et al.
An apoptosis panel for nonalcoholic steatohepatitis diagnosis
J Hepatol
(2011) - et al.
A population-based study on the prevalence of NASH using scores validated against liver histology
J Hepatol
(2014) - et al.
The MBOAT7 variant rs641738 alters hepatic phosphatidylinositols and increases severity of non-alcoholic fatty liver disease in humans
J Hepatol
(2016) - et al.
Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease
J Lipid Res
(2019) - et al.
Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis
J Hepatol
(2017) - et al.
Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese
Gastroenterology
(2001) - et al.
PNPLA3 mediates hepatocyte triacylglycerol remodeling
J Lipid Res
(2014) - et al.
Hepatic transmembrane 6 superfamily member 2 regulates cholesterol metabolism in mice
Gastroenterology
(2016)
Inactivation of Tm6sf2, a gene defective in fatty liver disease, impairs lipidation but not secretion of very low density lipoproteins
J Biol Chem
Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis
N Engl J Med
Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening
Gastroenterology
EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
J Hepatol
The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases
Hepatology
Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease
J Gastroenterol Hepatol
Cited by (32)
Long-Term Effect of PNPLA3 on the Aggravation of Nonalcoholic Fatty Liver Disease in a Biopsy-Proven Cohort
2023, Clinical Gastroenterology and HepatologyMembrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease
2022, Journal of Lipid ResearchCitation Excerpt :It is important to note that the rs626283 SNP is in strong linkage disequilibrium with rs641738 across numerous studies (23). Although the majority of large studies find a clear association between MBOAT7 loss of function and NAFLD progression, it is important to point out that not all studies have found statistically significant associations (24–35). Although consistent trends in association exist, several independent studies looking at NAFLD-related indices in adults (24–31) and children (32–35) have failed to conclude that the rs641738 SNP is associated with NAFLD progression.
Genetic and epigenetic factors determining NAFLD risk
2021, Molecular MetabolismCitation Excerpt :The scoring system (NASH PNPLA3-TM6SF2 score, NASH-PT) was based on risk alleles of PNPLA3 rs738409 (C > G) and TM6SF2 rs58542926 (G > A), diabetes status, insulin resistance, and levels of AST and C-reactive protein. NASH-PT scores identified patients with NASH with a ROC-AUC between 0.787 and 0.859 [92]. In a cohort of 514 obese children and adolescents in which almost 70% of the participants were diagnosed with NAFLD by ultrasonography, Zusi et al. tested 11 genes and detected highly significant associations with risk alleles of PNPLA3 rs738409 (C > G), TM6SF2 rs58542926 (G > A), and GCKR rs1260326 (C > T) and a weaker association with a polymorphism of ELOVL2 rs2236212 (G > C) with a higher risk of NAFLD [93].
The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease
2021, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :These investigators also showed that the A/A genotype of HSD17B13 was significantly associated with lower rates of liver-related mortality, and with lower serum alanine aminotransferase levels, especially in people with obesity, in heavy drinkers and in individuals carrying three or four steatogenic alleles in the PNPLA3 and TM6SF2 genes [15]. In our study, we did not find any significant association between the HSD17B13 rs72613567 variant and the presence of NASH or the individual histological components of NASH, which is also consistent with the results recently reported by Koo et al. in a cohort of 453 South Korean individuals with biopsy-proven NAFLD [29]. Currently, a significant association between the HSD17B13 rs72612567 variant and NAFLD has been reported only in Caucasian individuals [13,30,31].
Reply
2021, Clinical Gastroenterology and HepatologyExternal Validation of the Nonalcoholic Steatohepatitis Scoring System in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease in China
2021, Clinical Gastroenterology and Hepatology
CRediT Authorship Contributions Bo Kyung Koo (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Validation: Lead; Writing – original draft: Lead; Writing – review and editing: Lead) Sae Kyung Joo (Data curation: Lead; Formal analysis: Equal; Investigation: Lead; Resources: Lead) Donghee Kim (Conceptualization: Supporting; Supervision: Equal; Writing – original draft: Supporting; Writing – review and editing: Equal) Seonhwa Lee (Investigation: Supporting; Methodology: Supporting; Resources: Supporting) Jeong Mo Bae (Formal analysis: Supporting; Investigation: Lead; Resources: Lead) Jeong Hwan Park (Formal analysis: Supporting; Investigation: Lead; Resources: Equal) Jung Ho Kim (Formal analysis: Equal; Investigation: Lead; Resources: Equal) Mee Soo Chang (Formal analysis: Equal; Investigation: Equal; Resources: Supporting; Supervision: Equal) Won Kim, MD, PhD (Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Supervision: Lead; Validation: Lead; Writing – original draft: Lead; Writing – review and editing: Lead)
Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by a National Research Foundation of Korea grant funded by the Korea government (MEST) (2016R1D1A1B04934590), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (H I17C0912). The funding did not affect the collection, analysis, or presentation of the data.