Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese

Autor: Ryo Yamada, Toshiji Saibara, Yasuharu Imai, Fumihiko Matsuda, Miwa Kawanaka, Kohichiroh Yasui, Toshihide Shima, Hideo Tanaka, Atsushi Umemura, Sumio Watanabe, Etsuko Hashimoto, Hyohun Park, Takahisa Kawaguchi, Meiko Takahashi, Toshinari Takamura, Sumio Kawata, Kazuo Tajima, Yoshio Sumida, Keitaro Matsuo, Miki Kokubo
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Male
Pathology
Cirrhosis
Epidemiology
Chromosomes
Human
Pair 22
lcsh:Medicine
Genome-wide association study
Nonalcoholic Steatohepatitis
Gastroenterology
Severity of Illness Index
Biochemistry
Japan
Fibrosis
Nonalcoholic fatty liver disease
lcsh:Science
education.field_of_study
Molecular Epidemiology
Multidisciplinary
Liver Diseases
Fatty liver
Middle Aged
Lipids
Genetic Epidemiology
Medicine
Female
Research Article
Adult
medicine.medical_specialty
Population
Immunology
Single-nucleotide polymorphism
Gastroenterology and Hepatology
Biology
Polymorphism
Single Nucleotide
Internal medicine
medicine
Genetics
Genome-Wide Association Studies
Humans
Obesity
education
Nutrition
Inflammation
lcsh:R
Case-control study
Immunity
Membrane Proteins
nutritional and metabolic diseases
Human Genetics
Lipase
medicine.disease
Lipid Metabolism
digestive system diseases
Fatty Liver
Metabolism
Case-Control Studies
Clinical Immunology
lcsh:Q
Genome-Wide Association Study
Zdroj: PLoS ONE, Vol 7, Iss 6, p e38322 (2012)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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