Genetic Polymorphisms of the Human PNPLA3 Gene Are Strongly Associated with Severity of Non-Alcoholic Fatty Liver Disease in Japanese

<div><h3>Background</h3><p>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.</p> <h3>Principal Findings</h3><p>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 <em>PNPLA3</em> on chromosome 22q13 with the strongest <em>p</em>-value of 1.4×10<sup>−10</sup> (OR = 1.66, 95%CI: 1.43–1.94) for rs738409. Rs738409 also showed the strongest association (<em>p</em> = 3.6×10<sup>−6</sup>) 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 (<em>p</em> = 4.8×10<sup>−6</sup>, 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 (<em>p</em> = 1.7×10<sup>−16</sup>, OR = 2.18, 95%CI: 1.81–2.63) whereas no association was obtained for type1 to type3 (<em>p</em> = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (<em>p</em> = 4.6×10<sup>−4</sup>), HbA1c (<em>p</em> = 0.0011) and iron deposition in the liver (<em>p</em> = 5.6×10<sup>−4</sup>).</p> <h3>Conclusions</h3><p>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 <em>PNPLA3</em> gene is strongly associated with the progression of NASH in Japanese population.</p> </div>