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Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791941/ https://www.ncbi.nlm.nih.gov/pubmed/29385134 http://dx.doi.org/10.1371/journal.pone.0185490 |
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author | Kawaguchi, Takahisa Shima, Toshihide Mizuno, Masayuki Mitsumoto, Yasuhide Umemura, Atsushi Kanbara, Yoshihiro Tanaka, Saiyu Sumida, Yoshio Yasui, Kohichiro Takahashi, Meiko Matsuo, Keitaro Itoh, Yoshito Tokushige, Katsutoshi Hashimoto, Etsuko Kiyosawa, Kendo Kawaguchi, Masanori Itoh, Hiroyuki Uto, Hirofumi Komorizono, Yasuji Shirabe, Ken Takami, Shiro Takamura, Toshinari Kawanaka, Miwa Yamada, Ryo Matsuda, Fumihiko Okanoue, Takeshi |
author_facet | Kawaguchi, Takahisa Shima, Toshihide Mizuno, Masayuki Mitsumoto, Yasuhide Umemura, Atsushi Kanbara, Yoshihiro Tanaka, Saiyu Sumida, Yoshio Yasui, Kohichiro Takahashi, Meiko Matsuo, Keitaro Itoh, Yoshito Tokushige, Katsutoshi Hashimoto, Etsuko Kiyosawa, Kendo Kawaguchi, Masanori Itoh, Hiroyuki Uto, Hirofumi Komorizono, Yasuji Shirabe, Ken Takami, Shiro Takamura, Toshinari Kawanaka, Miwa Yamada, Ryo Matsuda, Fumihiko Okanoue, Takeshi |
author_sort | Kawaguchi, Takahisa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5791941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-57919412018-02-14 Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers Kawaguchi, Takahisa Shima, Toshihide Mizuno, Masayuki Mitsumoto, Yasuhide Umemura, Atsushi Kanbara, Yoshihiro Tanaka, Saiyu Sumida, Yoshio Yasui, Kohichiro Takahashi, Meiko Matsuo, Keitaro Itoh, Yoshito Tokushige, Katsutoshi Hashimoto, Etsuko Kiyosawa, Kendo Kawaguchi, Masanori Itoh, Hiroyuki Uto, Hirofumi Komorizono, Yasuji Shirabe, Ken Takami, Shiro Takamura, Toshinari Kawanaka, Miwa Yamada, Ryo Matsuda, Fumihiko Okanoue, Takeshi PLoS One Research Article 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. Public Library of Science 2018-01-31 /pmc/articles/PMC5791941/ /pubmed/29385134 http://dx.doi.org/10.1371/journal.pone.0185490 Text en © 2018 Kawaguchi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Kawaguchi, Takahisa Shima, Toshihide Mizuno, Masayuki Mitsumoto, Yasuhide Umemura, Atsushi Kanbara, Yoshihiro Tanaka, Saiyu Sumida, Yoshio Yasui, Kohichiro Takahashi, Meiko Matsuo, Keitaro Itoh, Yoshito Tokushige, Katsutoshi Hashimoto, Etsuko Kiyosawa, Kendo Kawaguchi, Masanori Itoh, Hiroyuki Uto, Hirofumi Komorizono, Yasuji Shirabe, Ken Takami, Shiro Takamura, Toshinari Kawanaka, Miwa Yamada, Ryo Matsuda, Fumihiko Okanoue, Takeshi Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title | Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title_full | Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title_fullStr | Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title_full_unstemmed | Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title_short | Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers |
title_sort | risk estimation model for nonalcoholic fatty liver disease in the japanese using multiple genetic markers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791941/ https://www.ncbi.nlm.nih.gov/pubmed/29385134 http://dx.doi.org/10.1371/journal.pone.0185490 |
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