TY - JOUR
T1 - An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval
AU - Kapoor, Ashish
AU - Sekar, Rajesh B.
AU - Hansen, Nancy F.
AU - Fox-Talbot, Karen
AU - Morley, Michael
AU - Pihur, Vasyl
AU - Chatterjee, Sumantra
AU - Brandimarto, Jeffrey
AU - Moravec, Christine S.
AU - Pulit, Sara L.
AU - Pfeufer, Arne
AU - Mullikin, Jim
AU - Ross, Mark
AU - Green, Eric D.
AU - Bentley, David
AU - Newton-Cheh, Christopher
AU - Boerwinkle, Eric
AU - Tomaselli, Gordon F.
AU - Cappola, Thomas P.
AU - Arking, Dan E.
AU - Halushka, Marc K.
AU - Chakravarti, Aravinda
N1 - Funding Information:
We are grateful to William C. Claycomb (Louisiana State University, New Orleans) for providing HL1 cells, Norman Barker (Johns Hopkins University, Baltimore) for help with imaging, and Akhilesh Pandey and Andrew S. McCallion (Johns Hopkins University, Baltimore) for critical discussions. We also thank Ashley O’Connor and Maria X. Sosa (Johns Hopkins University, Baltimore) for technical assistance, Paula Kokko-Gonzales, Louise Fraser, Niall Gormley, and Terena James (Illumina) for sequencing, and Ankit Rakha (Johns Hopkins University, Baltimore), Keira Cheetham, and Lisa Murray (Illumina) for computational support. This work was supported by NIH grants RO1HL086694 and RO1HL105993 and funds from the Donald W. Reynolds Foundation. A.C. is on the Scientific Advisory Board of Biogen Idec and this potential competing interest is managed by the policies of the Johns Hopkins University, School of Medicine. M.R. and D.B. are employees of Illumina, Inc., a public company that develops and markets systems for genetic analysis.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
AB - QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
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U2 - 10.1016/j.ajhg.2014.05.001
DO - 10.1016/j.ajhg.2014.05.001
M3 - Article
C2 - 24857694
AN - SCOPUS:84902245734
SN - 0002-9297
VL - 94
SP - 854
EP - 869
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -