1. Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese.
- Author
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Kawaguchi, Takahisa, Sumida, Yoshio, Umemura, Atsushi, Matsuo, Keitaro, Takahashi, Meiko, Takamura, Toshinari, Yasui, Kohichiroh, Saibara, Toshiji, Hashimoto, Etsuko, Kawanaka, Miwa, Watanabe, Sumio, Kawata, Sumio, Imai, Yasuharu, Kokubo, Miki, Shima, Toshihide, Park, Hyohun, Tanaka, Hideo, Tajima, Kazuo, Yamada, Ryo, and Matsuda, Fumihiko
- Subjects
GENETIC polymorphisms ,POPULATION genetics ,FATTY liver ,CIRRHOSIS of the liver ,GENETICS - Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle. Principal Findings: To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4×10
-10 (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6×10-6 ) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory- Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8×10-6 , OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7×10-16 , OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6×10-4 ), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6×10-4 ). Conclusions: With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population. [ABSTRACT FROM AUTHOR]- Published
- 2012
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