Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population

Mitsuru Matsukura; Kouichi Ozaki; Atsushi Takahashi; Yoshihiro Onouchi; Takashi Morizono; Hiroyoshi Komai; Hiroshi Shigematsu; Toshifumi Kudo; Yoshinori Inoue; Hideo Kimura; Akihiro Hosaka; Kunihiro Shigematsu; Teturo Miyata; Toshiaki Watanabe; Tatsuhiko Tsunoda; Michiaki Kubo; Toshihiro Tanaka

doi:10.1371/journal.pone.0139262

Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population

PLoS One. 2015 Oct 21;10(10):e0139262. doi: 10.1371/journal.pone.0139262. eCollection 2015.

Authors

Mitsuru Matsukura¹, Kouichi Ozaki², Atsushi Takahashi³, Yoshihiro Onouchi², Takashi Morizono⁴, Hiroyoshi Komai⁵, Hiroshi Shigematsu⁶, Toshifumi Kudo⁷, Yoshinori Inoue⁸, Hideo Kimura⁹, Akihiro Hosaka¹⁰, Kunihiro Shigematsu¹¹, Teturo Miyata¹², Toshiaki Watanabe¹³, Tatsuhiko Tsunoda⁴, Michiaki Kubo¹⁴, Toshihiro Tanaka¹⁵

Affiliations

¹ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
² Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴ Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵ Unit of Peripheral Vascular Surgery, Department of Surgery, Kansai Medical University, Osaka, Japan.
⁶ Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan.
⁷ Department of Professional Development, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Vascular Surgery, Department of Esophageal and General Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Department of Surgery, Manaka-hospital, Kanagawa, Japan.
¹⁰ Department of Surgery, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
¹¹ Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹² Sanno Hospital and Sanno Medical Center, Vascular Center, Tokyo, Japan.
¹³ Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁴ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹⁵ Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Characteristics of peripheral arterial disease (PAD) are the occlusion or stenosis of multiple vessel sites caused mainly by atherosclerosis and chronic lower limb ischemia. To identify PAD susceptible loci, we conducted a genome-wide association study (GWAS) with 785 cases and 3,383 controls in a Japanese population using 431,666 single nucleotide polymorphisms (SNP). After staged analyses including a total of 3,164 cases and 20,134 controls, we identified 3 novel PAD susceptibility loci at IPO5/RAP2A, EDNRA and HDAC9 with genome wide significance (combined P = 6.8 x 10-14, 5.3 x 10-9 and 8.8 x 10-8, respectively). Fine-mapping at the IPO5/RAP2A locus revealed that rs9584669 conferred risk of PAD. Luciferase assay showed that the risk allele at this locus reduced expression levels of IPO5. To our knowledge, these are the first genetic risk factors for PAD.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aorta / cytology
Aorta / metabolism
Case-Control Studies
Cells, Cultured
Chromosome Mapping
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study*
Histone Deacetylases / genetics*
Humans
Japan / epidemiology
Luciferases / metabolism
Male
Middle Aged
Myocytes, Smooth Muscle / cytology
Myocytes, Smooth Muscle / metabolism
Peripheral Arterial Disease / epidemiology
Peripheral Arterial Disease / genetics*
Polymorphism, Single Nucleotide / genetics*
Receptor, Endothelin A / genetics*
Repressor Proteins / genetics*
Risk Factors
beta Karyopherins / genetics*
rap GTP-Binding Proteins / genetics*

Substances

IPO5 protein, human
Receptor, Endothelin A
Repressor Proteins
beta Karyopherins
Luciferases
HDAC9 protein, human
Histone Deacetylases
RAP2A protein, human
rap GTP-Binding Proteins

Grants and funding

The Ministry of Education, Culture, Sports, Sciences and Technology from the Japanese Government (https://www.jsps.go.jp/j-grantsinaid/). The Astellas Foundation for Research on Metabolic Disorders (http://www.astellas.com/jp/byoutai/assist/gist.html). The Naito Foundation (https://www.naito-f.or.jp/jp/index.php). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.