C-3-06

Association of CDKN2A/B, ADTRP and PDGFD
polymorphisms with coronary atherosclerosis in Japan123

Sariya Dechamethakun 1

Shinobu Ikeda 1

Tomio Arai 2

dsariya.epi@mri.tmd.ac.jp

sikeda.epi@mri.tmd.ac.jp

arai@tmig.or.jp

Noriko Sato 1

Masaaki Muramatsu 1

Motoji Sawabe 3

nsato.epi@tmd.ac.jp

muramatsu.epi@mri.tmd.ac.jp

m.sawabe.mptmd.ac.jp

Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental
University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology,35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan
Section of Molecular Pathology, Graduate School of Health Care Sciences, Tokyo Medical andDental University, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan

Keywords: coronary artery disease (CAD), myocardial infraction (MI), pathology
Background: Genome-wide association studies have identified a series of susceptibility loci forcoronary artery disease (CAD). Our study attempted to replicate the results for eight of these loci,
CDKN2A/B (rs1333049), ADTRP (rs6903956), PDGFD (rs974819), TCF21 (rs12190287),
COL4A1-A2 (rs4773144), HHIPL1 (rs2895811), ADAMTS7 (rs4380028), and UBE2Z (rs46522), in
pathologically defined atherosclerosis of the coronary artery. Methods: Autopsy cases of elderly
Japanese subjects were enrolled in the JG-SNP study (n=1536). Polymorphisms were genotyped,
and their association with coronary stenosis index (CSI) and pathologi cal myocardial infraction(MI) was investigated. Potential combinatorial effects of susceptibility loci were also investigated.
Results: Among the eight loci tested, three gave a sign of positive association. CDKN2A/B showed
the most robust association with CSI and MI (p=0.007 and OR=1.843, 95% CI 1.293-2.629,
p=0.001, for CC+CG vs. GG). ADTRP showed association with CSI and MI, but the risk allele wasopposite from the original report (p =0.008 and OR=1.652, 95% CI 1.027-2.656, p =0.038 for GG
vs. AA+AG). PDGFD showed a suggestive association with CSI in females , but not in males (p=0.023). CDKN2A/B, and ADTRP were significantly associated with severity of CSI, in acase-control setting (top 75% vs. the rest: OR=1.683, 95% CI 1.219-2.323, p =0.002 for CC+CG vs.
GG, OR=1.839, 95% CI 1.172-2.886, p =0.008 for GG vs. AA+AG, respectively). The cumulativerisk allele counting of CDKN2A/B, ADTRP, and PDGFD indicated that increasing number of risk
alleles associated with higher CSI (p <0.001). Conclusions: Our data confirms the association ofCDKN2A/B with CAD, and suggests a different associated risk allele of ADTRP. PDGFD shows agender specific association to CAD. The combination of multiple risk alleles may associate withhigher risk of CAD.
[1] Schunkert, H., et al., Large-scale association analysis identifies 13 new susceptibility loci forcoronary artery disease, Nature Genetics, 6;43(4):333-8, 2011.
[2] Peden, J.F., et al., A genome-wide association study in Europeans and South Asians identifies
five new loci for coronary artery disease, Nature Genetics, 6;43(4):339-44, 2011.
[3] Wang, F., et al., Genome-wide association identifies a susceptibility locus for coronary arterydisease in the Chinese Han population, Nature Genetics, 6;43(4):345-9, 2011.