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

BackgroundNonalcoholic 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 FindingsTo 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).
ConclusionsWith 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.

研究背景：非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）涵盖了从单纯性脂肪变性到肝硬化、纤维化的一系列广泛肝脏病理改变，其中伴随肝细胞变性与纤维化的亚型被归类为非酒精性脂肪性肝炎（nonalcoholic steatohepatitis, NASH）。NASH约占NAFLD患者的10%~30%，且肝相关死亡发生率更高；目前认为NASH的疾病进程较为复杂，涉及多种遗传因素与环境及生活方式的相互作用。

主要研究结果：为鉴定日本人群中与NAFLD相关的遗传因素，本研究开展全基因组关联研究，招募了529例经组织学确诊的NAFLD患者与932名人群对照。在22号染色体q13区域的PNPLA3基因簇的单核苷酸多态性（single nucleotide polymorphism, SNP）位点中观察到显著关联，其中rs738409的最小关联p值为1.4×10^−10，比值比（odds ratio, OR）=1.66，95%置信区间（confidence interval, CI）为1.43~1.94。rs738409同样与Matteoni及其同事基于炎症程度、气球样变性、纤维化及马洛里-登克小体提出的组织学分类标准表现出最强关联（p=3.6×10^−6）。此外，对应NASH的4型亚组与其余三个亚组之间，rs738409的基因型分布存在显著差异（p=4.8×10^−6，OR=1.96，95%CI:1.47~2.62）。进一步针对NAFLD患者与对照的亚组分析显示，rs738409与4型NAFLD存在显著关联（p=1.7×10^−16，OR=2.18，95%CI:1.81~2.63），而与1至3型NAFLD无显著关联（p=0.41）。rs738409还与三项与NAFLD预后相关的临床指标存在强关联：透明质酸水平（p=4.6×10^−4）、糖化血红蛋白A1c（HbA1c）水平（p=0.0011）及肝脏铁沉积量（p=5.6×10^−4）。

研究结论：基于上述研究结果，本研究明确证实Matteoni 4型NAFLD是一类在遗传与临床层面均区别于该疾病其他表型谱的独特亚组，且PNPLA3基因与日本人群中NASH的疾病进展存在强关联。