Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population.
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.
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.
Mitsuru
M
Matsukura
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Kouichi
K
Ozaki
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Atsushi
A
Takahashi
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Yoshihiro
Y
Onouchi
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Takashi
T
Morizono
Unit of Peripheral Vascular Surgery, Department of Surgery, Kansai Medical University, Osaka, Japan.
Hiroyoshi
H
Komai
Clinical Research Center for Medicine, International University of Health and Welfare, Tokyo, Japan.
Hiroshi
H
Shigematsu
Department of Professional Development, Tokyo Medical and Dental University, Tokyo, Japan.
Toshifumi
T
Kudo
Department of Vascular Surgery, Department of Esophageal and General Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
Yoshinori
Y
Inoue
Department of Surgery, Manaka-hospital, Kanagawa, Japan.
Hideo
H
Kimura
Department of Surgery, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
Akihiro
A
Hosaka
Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Kunihiro
K
Shigematsu
Sanno Hospital and Sanno Medical Center, Vascular Center, Tokyo, Japan.
Teturo
T
Miyata
Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Toshiaki
T
Watanabe
Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Tatsuhiko
T
Tsunoda
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Michiaki
M
Kubo
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
Toshihiro
T
Tanaka
D000368:Aged; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002874:Chromosome Mapping; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044022:Receptor, Endothelin A / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D028961:beta Karyopherins / Q000235:genetics*; D020668:rap GTP-Binding Proteins / Q000235:genetics*
C107940:IPO5 protein, human; D044022:Receptor, Endothelin A; D012097:Repressor Proteins; D028961:beta Karyopherins; D008156:Luciferases; C486544:HDAC9 protein, human; D006655:Histone Deacetylases; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins