1. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers
- Author
-
Yasuji Komorizono, Toshinari Takamura, Kohichiro Yasui, Keitaro Matsuo, Yoshito Itoh, Toshihide Shima, Yoshihiro Kanbara, Yoshio Sumida, Yasuhide Mitsumoto, Masanori Kawaguchi, Hirofumi Uto, Ken Shirabe, Masayuki Mizuno, Takahisa Kawaguchi, Takeshi Okanoue, Atsushi Umemura, Fumihiko Matsuda, Katsutoshi Tokushige, Etsuko Hashimoto, Ryo Yamada, Hiroyuki Itoh, Kendo Kiyosawa, Miwa Kawanaka, Meiko Takahashi, Saiyu Tanaka, and Shiro Takami
- Subjects
0301 basic medicine ,Heredity ,lcsh:Medicine ,Genome-wide association study ,Gastroenterology ,Genome-wide association studies ,0302 clinical medicine ,Japan ,Human genetics ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Nonalcoholic fatty liver disease ,Medicine and Health Sciences ,Molecular genetics ,lcsh:Science ,Genetics of disease ,Multidisciplinary ,Liver Diseases ,Fatty liver ,Liver Neoplasms ,Genomics ,Genetic Mapping ,Hepatocellular carcinoma ,030211 gastroenterology & hepatology ,Anatomy ,Research Article ,Genetic Markers ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Histology ,Single-nucleotide polymorphism ,Gastroenterology and Hepatology ,Models, Biological ,Polymorphism, Single Nucleotide ,digestive system ,03 medical and health sciences ,Internal medicine ,medicine ,Genetics ,SNP ,Humans ,Genetic Predisposition to Disease ,Allele ,Nonalcoholic steatohepatitis ,Variant genotypes ,Molecular Biology ,Alleles ,business.industry ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,nutritional and metabolic diseases ,medicine.disease ,Genome Analysis ,digestive system diseases ,030104 developmental biology ,Genetic marker ,lcsh:Q ,business ,Genome-Wide Association Study - 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., 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.
- Published
- 2018