A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes

Makiko Taira; Minako Imamura; Atsushi Takahashi; Yoichiro Kamatani; Toshimasa Yamauchi; Shin-Ichi Araki; Nobue Tanaka; Natalie R van Zuydam; Emma Ahlqvist; Masao Toyoda; Tomoya Umezono; Koichi Kawai; Masahito Imanishi; Hirotaka Watada; Daisuke Suzuki; Hiroshi Maegawa; Tetsuya Babazono; Kohei Kaku; Ryuzo Kawamori; SUMMIT Consortium; Leif C Groop; Mark I McCarthy; Takashi Kadowaki; Shiro Maeda

doi:10.1371/journal.pone.0208654

A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes

PLoS One. 2018 Dec 19;13(12):e0208654. doi: 10.1371/journal.pone.0208654. eCollection 2018.

Authors

Makiko Taira¹, Minako Imamura^{1

2

3}, Atsushi Takahashi^{4

5}, Yoichiro Kamatani^{4

6}, Toshimasa Yamauchi⁷, Shin-Ichi Araki⁸, Nobue Tanaka⁹, Natalie R van Zuydam^{10

11}, Emma Ahlqvist¹², Masao Toyoda¹³, Tomoya Umezono¹³, Koichi Kawai¹⁴, Masahito Imanishi^{15

16}, Hirotaka Watada^{17

18}, Daisuke Suzuki¹⁹, Hiroshi Maegawa⁸, Tetsuya Babazono⁹, Kohei Kaku²⁰, Ryuzo Kawamori¹⁸; SUMMIT Consortium; Leif C Groop^{12

21}, Mark I McCarthy^{10

11

22}, Takashi Kadowaki^{7

23

24}, Shiro Maeda^{1

2

3}

Affiliations

¹ Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
² Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
³ Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa, Japan.
⁴ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
⁵ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁶ Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁷ Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
⁹ Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
¹⁰ Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
¹¹ Oxford Center for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
¹² Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Scania University Hospital, Malmö, Sweden.
¹³ Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.
¹⁴ Kawai Clinic, Ibaragi, Japan.
¹⁵ Division of Nephrology and Hypertension, Department of Internal Medicine, Osaka City General Hospital, Osaka, Japan.
¹⁶ Department of Nephrology, and Hemodialysis Unit, Ishikiriseiki Hospital, Higashi-Osaka, Japan.
¹⁷ Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁸ Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
¹⁹ Suzuki Diabetes Clinic, Kanagawa, Japan.
²⁰ Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
²¹ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
²² Oxford NIHR BIOMEDICAL Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
²³ Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁴ Department of Metabolism and Nutrition, Mizonokuchi Hospital, Faculty of Medicine, Teikyo University, Kanagawa, Japan.

Abstract

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
Case-Control Studies
Diabetes Mellitus, Type 2 / genetics*
Diabetic Nephropathies / genetics*
Female
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Japan
Male
Middle Aged
Polymorphism, Single Nucleotide*

Substances

Alpha-Ketoglutarate-Dependent Dioxygenase FTO
FTO protein, human

Grants and funding

This work was partly supported by a grant from the Ministry of Education, Culture, Science and Technology, Japan (to SM), and from the Japan Agency of Medical Research and Development (17km0405202h0802) (TK, TY, SM). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n° 115006, the SUMMIT Consortium.