REPORT A Common Variant in SLC8A1 Is Associated with the Duration of the Electrocardiographic QT Interval Jong Wook Kim, 1,2,8 Kyung-Won Hong, 1,8 Min Jin Go, 1 Sung Soo Kim, 1 Yasuharu Tabara, 3 Yoshikuni Kita, 4 Takeshi Tanigawa, 5 Yoon Shin Cho, 1,6 Bok-Ghee Han, 1, * and Bermseok Oh 7, * Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, predisposes one to ventricular arrhythmias and sudden cardiac death. Since NOS1AP , a regulator of neuronal nitric oxide synthase, was discovered in a genome-wide association study (GWAS) as a novel target that modulates cardiac repolarization, several loci have been linked to the QT interval in studies (QTGEN and QTSCD) of European descendents. However, there has been no GWAS of the QT interval in Asian populations. We conducted a GWAS with regard to the QT interval in Korea Association Resource (KARE [n ¼ 6,805]) cohorts. Replication studies in independent populations of Korean (n ¼ 4,686) and Japanese (n ¼ 2,687) groups validated the association between a SNP, rs13017846, which maps to near SLC8A1 (sodium/calcium exchanger 1 precursor, overall p ¼ 8.0 3 10 À14 ), and the QT interval. The minor allele frequency (MAF) of rs13017846 varies widely between ethnicities—0.053 in Europeans (HapMap CEU [Utah residents with ancestry from northern and western Europe from the Centre d 0 E ´ tude du Polymorphisme Humain collection] samples) versus 0.080 in Africans (HapMap YRI [Yoruba in Ibadan, Nigeria] samples)—whereas a MAF of 0.500 has been reported in Asians (HapMap HCB [Han Chinese in Beijing, China] and JPT [Japanese in Tokyo, Japan] samples). This might explain why this locus has not been identified in Europeans in previous studies. Sudden cardiac death by acute ventricular arrhythmia is a common cause of mortality in developed countries. 1,2 Prolongation of ventricular repolarization increases the risk of ventricular arrhythmia, as observed in congenital long QT syndrome (LQTS), a rare Mendelian disorder. 3 The QT interval—the span between the start of the Q wave and the end of the T wave of the cardiac electrical cycle—is the traditional measure of the duration of ventric- ular depolarization and repolarization 4 and is genetically influenced (it has approximately 50% heritability). 5,6 Since NOS1AP (MIM 610141), a regulator of neuronal ni- tric oxide synthase, was identified in a genome-wide asso- ciation study (GWAS) as a novel target that modulates cardiac repolarization, 7 several loci have been linked to the QT interval in studies (QTGEN and QTSCD) of Euro- pean descendents. 8,9 However, no GWAS on the QT interval has been performed on Asian populations. To understand the genetic architecture of QT intervals in Asians, we conducted a GWAS by using data from Korea Association Resource (KARE [phase 1, n ¼ 6,805]) 10 during the discovery phase and two subsequent replication studies (phase 2) in independent Korean (n ¼ 4,686) and Japanese (n ¼ 2,687) populations. The studies from which this report collected data acquired informed consent from all participants and were approved by the appropriate ethics committees at the respective institu- tions and countries. The overall study design is shown in Figure S1, available online. Of the 8,842 original KARE discovery-phase partic- ipants, those who had missing electrocardiographic data were excluded (n ¼ 1,713). Also, participants with a history of ischemic heart disease, stroke, coronary-artery bypass surgery, or electrocardiographic findings, such as atrial fibrillation, QRS duration > 120 ms, right or left bundle-branch block, and frequent ventricular premature beats >10% of the beats, were excluded (n ¼ 324). Partici- pants with electrocardiogram (ECG) abnormalities, as defined by the presence of Minnesota codes 1.1, 1.2 (major Q wave), 4 or 5 (ST and T wave changes), 7.1–7.6 (ventric- ular-conduction defect), or 8.1 (frequent atrial or ventric- ular premature contraction) to 8.3 (atrial fibrillation or flutter), 11 were excluded from the analysis. We also excluded subjects who were being treated with medica- tions that were likely to modify the duration of the QT interval (n ¼ 34). 4 The final number of subjects for the GWAS was 6,805. The same exclusion criteria were applied for the phase 2 replication studies, although the population characteris- tics and genotyping platforms varied between studies (Tables S1 and S2 and Figure S2). To measure QT intervals in the phase 1 study, we ob- tained a supine 12-lead ECG by using a MAC 5000 (GE Medical System, CT, USA). On the basis of the 12-lead ECG, the QT interval was measured from the earliest onset 1 Center for Genome Science, National Institutes of Health, Korea Centers for Disease Control and Prevention, Osong 363-951, Korea; 2 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea; 3 Department of Basic Medical Research and Educa- tion, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; 4 Department of Health Science, Shiga University of Medical Science, Otsu 520-2192, Japan; 5 Department of Public Health, Ehime University Graduate School of Medicine, Toon 791-0295, Japan; 6 Department of Biomedical Science, Hallym University, Chuncheon 200-702, Korea; 7 Department of Biomedical Engineering, School of Medicine, Kyung Hee University, Seoul 130-701, Korea 8 These authors contributed equally to this work *Correspondence: bokghee@korea.kr (B.-G.H.), ohbs@khu.ac.kr (B.O.) DOI 10.1016/j.ajhg.2012.05.019. Ó2012 by The American Society of Human Genetics. All rights reserved. 180 The American Journal of Human Genetics 91, 180–184, July 13, 2012