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Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan

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Abstract

We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10−14, OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10−10) and high odds ratios (1.84–2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.

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Acknowledgments

This work was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan (21591186 to K. H, 23791027 to A. K., and 23701082 to T. K.).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. EBM Research Center, Kyoto University Graduate School of Medicine, Yoshida-Konoecho, Sakyo-ku, Kyoto, 606-8501, Japan

    Takuya Kitamoto, Aya Kitamoto, Kazuwa Nakao, Akihiro Sekine & Kikuko Hotta

  2. Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Masato Yoneda & Atsushi Nakajima

  3. Division of Frontier Medical Science, Department of Medicine and Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    Hideyuki Hyogo, Hidenori Ochi & Kazuaki Chayama

  4. Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Japan

    Takahiro Nakamura

  5. Center for Genomic Medicine, Unit of Genome Informatics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Hajime Teranishi & Seiho Mizusawa

  6. Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan

    Takato Ueno

  7. Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Kazuwa Nakao

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  1. Takuya Kitamoto
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  2. Aya Kitamoto
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  11. Atsushi Nakajima
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  13. Akihiro Sekine
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Correspondence to Kikuko Hotta.

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Kitamoto, T., Kitamoto, A., Yoneda, M. et al. Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan. Hum Genet 132, 783–792 (2013). https://doi.org/10.1007/s00439-013-1294-3

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