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タイトル: Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers
著者: Kawaguchi, Takahisa
Shima, Toshihide
Mizuno, Masayuki
Mitsumoto, Yasuhide
Umemura, Atsushi
Kanbara, Yoshihiro
Tanaka, Saiyu
Sumida, Yoshio
Yasui, Kohichiro
Takahashi, Meiko  kyouindb  KAKEN_id
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  KAKEN_id  orcid https://orcid.org/0000-0002-1587-630X (unconfirmed)
Matsuda, Fumihiko  kyouindb  KAKEN_id
Okanoue, Takeshi
著者名の別形: 川口, 喬久
松田, 文彦
岡上, 武
キーワード: Genome-wide association studies
Fatty liver
Nonalcoholic steatohepatitis
Human genetics
Molecular genetics
Genetics of disease
Histology
Variant genotypes
発行日: 31-Jan-2018
出版者: Public Library of Science (PLoS)
誌名: PLOS ONE
巻: 13
号: 1
論文番号: e0185490
抄録: 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.
記述: 非アルコール性脂肪性肝疾患(NAFLD)関連疾患の疾患感受性遺伝子を用いたリスク予測 --全ゲノム関連解析によって4つの疾患感受性遺伝子を同定--. 京都大学プレスリリース. 2018-02-15.
著作権等: © 2018 Kawaguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/229128
DOI(出版社版): 10.1371/journal.pone.0185490
PubMed ID: 29385134
関連リンク: https://www.kyoto-u.ac.jp/ja/research-news/2018-02-15-2
出現コレクション:学術雑誌掲載論文等

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