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

被引：206

作者：

Kawaguchi, Takahisa ^{[1
,2
]}

Sumida, Yoshio ^{[3
]}

Umemura, Atsushi ^{[4
]}

Matsuo, Keitaro ^{[5
]}

Takahashi, Meiko ^{[1
]}

Takamura, Toshinari ^{[6
]}

Yasui, Kohichiroh ^{[7
]}

Saibara, Toshiji

Hashimoto, Etsuko ^{[9
]}

Kawanaka, Miwa ^{[10
]}

Watanabe, Sumio ^{[2
]}

Kawata, Sumio ^{[11
,12
]}

Imai, Yasuharu ^{[13
]}

Kokubo, Miki ^{[1
]}

Shima, Toshihide ^{[4
,8
]}

Park, Hyohun ^{[4
]}

Tanaka, Hideo ^{[5
]}

Tajima, Kazuo ^{[5
]}

Yamada, Ryo ^{[1
]}

Matsuda, Fumihiko ^{[1
,2
]}

Okanoue, Takeshi ^{[4
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan

[2] Kyoto Univ, Grad Sch Med, INSERM, U852, Kyoto, Japan

[3] Nara City Hosp, Ctr Digest & Liver Dis, Nara, Japan

[4] Saiseikai Suita Hosp, Ctr Gastroenterol & Hepatol, Suita, Osaka, Japan

[5] Aichi Canc Ctr, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan

[6] Kanazawa Univ, Grad Sch Med Sci, Dept Dis Control & Homeostasis, Kanazawa, Ishikawa, Japan

[7] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Gastroenterol & Hepatol, Kyoto, Japan

[8] Kochi Med Sch, Dept Gastroenterol & Hepatol, Kochi, Japan

[9] Tokyo Womens Med Univ, Dept Internal Med & Gastroenterol, Tokyo, Japan

[10] Kawasaki Med Sch, Kawasaki Hosp, Ctr Liver Dis, Okayama, Japan

[11] Juntendo Univ, Sch Med, Dept Gastroenterol, Tokyo 113, Japan

[12] Yamagata Univ, Sch Med, Dept Gastroenterol, Yamagata 99023, Japan

[13] Ikeda Municipal Hosp, Dept Internal Med, Ikeda, Osaka, Japan

来源：

PLOS ONE | 2012年 / 7卷 / 06期

关键词：

STEATOHEPATITIS; SUSCEPTIBILITY; VARIANT; I148M;

D O I：

10.1371/journal.pone.0038322

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 1.4x10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6x10(-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 = 4.8x10(-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 = 1.7x10(-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 = 4.6x10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6x10(-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.

引用

页数：10

共 26 条

[1]

Haploview: analysis and visualization of LD and haplotype maps [J].