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July 2, 2010 Original Article Advance Publication Journal of Atherosclerosis and Thrombosis Journal of Atherosclerosis and ThrombosisAccepted Vol.17, forNo.● publication: May 7, 20101 Published online: July 2, 2010 Original Article Identification of Evidence Suggestive of an Association with Peripheral Arterial Disease at the OSBPL10 Locus by Genome-Wide Investigation in the Japanese Population Hiroshi Koriyama1, Hironori Nakagami2, Tomohiro Katsuya1, 3, Ken Sugimoto1, Hidetoshi Yamashita2, Yoichi Takami1, Shiro Maeda4, Michiaki Kubo5, Atsushi Takahashi6, Yusuke Nakamura7, Toshio Ogihara8, Hiromi Rakugi1,Yasufumi Kaneda2, and Ryuichi Morishita3 1Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan 2Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Suita, Japan 3Division of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan 4Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Tokyo, Japan 5Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Japan 6Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Tokyo, Japan 7Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan 8Osaka General Medical Center, Osaka Prefectural Hospital Organization, Osaka, Japan Aim: Peripheral arterial disease (PAD) is a common cause of cardiovascular morbidity and an inde- pendent predictor of cardiovascular mortality. However, little is known about the genetic basis of PAD. To elucidate this, we performed a two-staged genome-wide association study in Japanese indi- viduals. Methods: We initially tested 222,285 single-nucleotide polymorphisms (SNPs). After the first screen- ing in a panel of 195 PAD cases and 1,358 controls, 2,696 SNPs (1.2%) were further genotyped in the second screening using another panel of 699 PAD cases and 1540 controls. In both screenings, controls were subjects affected with some diseases other than PAD. Results: When analyzed in the combined panel, the strongest signal of PAD association was observed at rs1902341 in the intron of OSBPL10 (p =4.7E-7 for trend test; OR=1.31, 95% CI 1.18−1.46). Also, PAD was modestly associated at several other loci such as rs2554503 in CSMD1 (p =5.7E-5; OR=1.32, 95% CI 1.15−1.51) or rs235243 in VSP13D (p =0.04; OR=1.18, 95% CI 1.01−1.37). Conclusion: Our genome-wide exploration identified suggestive evidence of PAD association at the OSBPL10 locus. Because the association has not reached a genome-wide significant level, further replication study is warranted for verification in the Japanese population. J Atheroscler Thromb, 2010; 17:000-000. Key words; Peripheral arterial disease, Genome-wide association study, OSBPL10 ties caused by blood flow dysfunction resulting from Introduction atherosclerosis. Known risk factors include hyperten- Peripheral arterial disease (PAD) is characterized sion, diabetes mellitus, dyslipidemia, smoking, and by pain, ulceration and necrosis of the lower extremi- ageing. PAD is a significant predictor of cardiovascular mortality and is associated with an increased risk of Address for correspondence: Tomohiro Katsuya, Division of 1-4) Clinical Gene Therapy, Osaka University Graduate School of stroke, myocardial infarction, and death . In partic- Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan ular, the risk of cardiovascular death over a 10-year 2) E-mail: [email protected] period is increased 6-fold in patients with PAD . In Received: November 2, 2009 high-risk groups, such as subjects over the age of 50 Accepted for publication: May 7, 2010 years with a history of diabetes or smoking and sub- Advance Publication Journal of Atherosclerosis and Thrombosis 2 Koriyama et al. Accepted for publication: May 7, 2010 OSBPL10 is Associated with PAD 3 Published online: July 2, 2010 jects over the age of 70 years, the prevalence of PAD is sent. The protocol was approved by the ethics com- over 25% in North America and Europe5). mittee of Osaka University and of each participating Despite its prevalence and the high social cost institution. attributed to PAD6), the genetic basis of PAD and the factors that determine its responsiveness to treatment SNP Genotyping Methods are yet to be understood. There are no genetic tests Using standard protocols, we extracted genomic available that reliably identify the subset of subjects DNA from peripheral blood leukocytes. In the first carrying inherited risk factors for developing PAD on stage, we genotyped 268,068 SNPs from autosomal a large scale7); however, three family studies to date chromosomes; these SNPs were selected as tagging have reported estimates of heritability of PAD and SNPs for the Japanese population from the JSNP 11) or thus its heritability could be suggested8-10). A logical HapMap database12) using high-density oligonucle- next step is to perform a more comprehensive and otide arrays (Perlegen Sciences) as described previ- unbiased scan of variations in all genes or in the entire ously. SNPs having a call rate ＞90% and no extreme genome using what is commonly referred to as a departure from Hardy-Weinberg Equilibrium (p＜10－6) genome-wide association study (GWAS). Thus, the were passed and used for the association study. In the aim of this study was to identify PAD-susceptible second study, genotyping was conducted using the genes through GWAS of SNPs. multiplex-PCR invader assay13) for PAD subjects and high-density oligonucleotide arrays (Perlegen Sciences) for control subjects. In the multiplex-PCR invader Methods assay, SNPs having a call rate ＞85% were passed and Study Participants used for the association study. Regarding the success BioBank Japan: For the GWAS, we selected case- rates of the multiplex-PCR invader assay ＞90% agree- control samples (cases 1 and 2, controls 1 and 2) from ment existed between the results of genotyping and subjects enrolled in BioBank Japan. The subjects were direct sequencing. recruited from several medical institutes in Japan, including Fukujuji Hospital, Iizuka Hospital, Iwate Statistical Analysis Medical University School of Medicine, Juntendo Statistical methods for determining associations University, National Hospital Organization Osaka and calculating LD coefficients (r 2) have been National Hospital, Nihon University, Nippon Medical described previously14). We performed the HWE test School, Osaka Medical Center for Cancer and Cardio- according to a method previously described15). The vascular Diseases, and Shiga University of Medical cut-off value for the HWE test in control groups was Science, The Cancer Institute Hospital of Japanese 0.000001 for the first stage and 0.01 for the second Foundation for Cancer Research, Tokushukai Hospi- stage; SNPs with p values less than the cut-off values tals and Tokyo Metropolitan Geriatric Hospital. of the HWE test were excluded from analysis. We ana- We selected peripheral arterial disease cases from lyzed the differences between case and control groups the individuals registered. We defined PAD as those with respect to the genotype distribution and allele with either stenosis on angiography of the lower limbs frequency in genome-wide screening (first or second or with ABI fulfilling the diagnostic criteria among stage) by Fisher’s exact test using dominant, recessive patients complaining of symptoms such as intermit- and allelic models with autosomal SNPs. tent claudication or pain in the lower limbs. (case 1, n =195; case 2, n =699). Control groups were 1,358 Results (control 1) and 1,540 individuals (control 2) regis- tered as subjects without apparent clinical symptoms Genome-Wide Association Study of PAD and having diseases other than PAD, includ- To identify variants associated with susceptibility ing bronchial asthma, myocardial infarction, breast to PAD, we performed a genome-wide case-control cancer, Basedow’s disease, cerebral infarction, cerebral study in 195 individuals with PAD (case 1) and 1,358 aneurysm, osteoporosis, heart failure, unstable angina, controls (control 1) collected from the BioBank Japan, pollinosis, type 2 diabetes, emphysema, atopic derma- and genotyped 268,068 SNPs, which covered approxi- titis, stomach cancer or liver cirrhosis. The control mately 56% of common SNPs in Japanese (flow dia- subject group includes 194 cases of diabetes, 194 of gram of study is shown in Table 1). We compared the cerebral infarction (control 1), 188 of myocardial allele frequencies of 222,285 successfully genotyped infarction, and 189 of unstable angina (control 2). SNPs (which covered approximately 46% of common All participants provided written informed con- SNPs in Japanese), and selected 4,000 SNPs showing Advance Publication Journal of Atherosclerosis and Thrombosis 2 Koriyama et al. OSBPL10 is Associated withAccepted PAD for publication: May 7, 20103 Published online: July 2, 2010 the lowest p values between the two groups. In a sec- Table 1. Flow diagram of study ond round of screening, we attempted to genotype Entry: these 4,000 SNPs in 699 individuals with PAD (case 2) 300,000 BioBank Japan including PAD patients and 1,540 controls (control 2) (stage 2), and success- fully obtained data for 2,696 SNPs. The results of ⬇ principal component analysis in stage 1 and 2 samples and HapMap samples revealed no evidence of popula- 1st screening: tion stratification between case and control groups 222,285 SNPs genotyped in 195 cases and 1358 controls throughout the present tests (Fig.1A, 1B, 1C). Base- line characteristics for the populations in this study ⬇ are shown in Table 2. SNPs that showed small p val- ues (allelic model p＜0.005 and/or dominant model 2nd screening: p＜0.005 and/or recessive model p＜0.005) in the sec- 2,696 SNPs genotyped in remaining 699 cases and 1540 controls A C B Fig.1. Samples in the 1st test (A), 2nd test (B) and in HapMap database were analyzed using the Smartpca program (Price et al. 2006), and the first (X axis) and 2nd (Y axis) principal components were plotted. Japanese samples were clearly plotted in a single cluster, except for one sample. One subject in the 1st test was halfway between Japanese and CEU.
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