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

Takahisa Kawaguchi; Toshihide Shima; Masayuki Mizuno; Yasuhide Mitsumoto; Atsushi Umemura; Yoshihiro Kanbara; Saiyu Tanaka; Yoshio Sumida; Kohichiro Yasui; Meiko Takahashi; Keitaro Matsuo; Yoshito Itoh; Katsutoshi Tokushige; Etsuko Hashimoto; Kendo Kiyosawa; Masanori Kawaguchi; Hiroyuki Itoh; Hirofumi Uto; Yasuji Komorizono; Ken Shirabe; Shiro Takami; Toshinari Takamura; Miwa Kawanaka; Ryo Yamada; Fumihiko Matsuda; Takeshi Okanoue

doi:10.1371/journal.pone.0185490

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

PLoS One. 2018 Jan 31;13(1):e0185490. doi: 10.1371/journal.pone.0185490. eCollection 2018.

Authors

Takahisa Kawaguchi¹, Toshihide Shima², Masayuki Mizuno², Yasuhide Mitsumoto², Atsushi Umemura², Yoshihiro Kanbara³, Saiyu Tanaka⁴, Yoshio Sumida⁴, Kohichiro Yasui⁵, Meiko Takahashi¹, Keitaro Matsuo⁶, Yoshito Itoh⁵, Katsutoshi Tokushige⁷, Etsuko Hashimoto⁷, Kendo Kiyosawa⁸, Masanori Kawaguchi⁹, Hiroyuki Itoh¹⁰, Hirofumi Uto¹¹, Yasuji Komorizono¹², Ken Shirabe¹³, Shiro Takami¹⁴, Toshinari Takamura¹⁵, Miwa Kawanaka¹⁶, Ryo Yamada¹, Fumihiko Matsuda¹, Takeshi Okanoue²

Affiliations

¹ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
² Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita, Japan.
³ Department of Surgery, Saiseikai Suita Hospital, Suita, Japan.
⁴ Center of Hepatology, Nara Municipal Hospital, Nara, Japan.
⁵ Department of Gastroenterology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
⁶ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Aichi, Japan.
⁷ Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
⁸ Department of Gastroenterology, Nagano Red Cross Hospital, Nagano, Japan.
⁹ Department of Gastroenterology, Saiseikai Wakayama Hospital, Wakayama, Japan.
¹⁰ Department of Gastroenterology, Kure Saiseikai Hospital, Kure, Japan.
¹¹ Digestive and Life-style Related Disease, Kagoshima University Graduate School of Medicine and Dental Science, Kagoshima, Japan.
¹² Department of Hepatology, Nanpuh Hospital, Kagoshima, Japan.
¹³ Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
¹⁴ Department of Gastroenterology, Otsu Municipal Hospital, Otsu, Japan.
¹⁵ Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
¹⁶ Center of Liver Disease, Kawasaki Hospital, Kawasaki Medical School, Okayama, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Carcinoma, Hepatocellular / genetics*
Genetic Markers*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Japan
Liver Neoplasms / genetics*
Models, Biological*
Non-alcoholic Fatty Liver Disease / epidemiology
Non-alcoholic Fatty Liver Disease / genetics*
Polymorphism, Single Nucleotide
Risk Factors

Substances

Genetic Markers

Grants and funding

This work was supported by the grant from Ministry of Labor and Welfare Japan [T.O., H20-Hepatitis-general-008], Core Research of Evolutional Science & Technology (CREST), Research Program on Hepatitis from Japan Agency for Medical Research and Development, AMED. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.