Four Genetic Loci Influencing Electrocardiographic Indices of Left Ventricular Hypertrophy

Sonia Shah, Christopher P. Nelson, Tom R. Gaunt, Pim van der Harst, Timothy Barnes, Peter S. Braund, Debbie A. Lawlor, Juan-Pablo Casas, Sandosh Padmanabhan, Fotios Drenos, Mika Kivimaki, Philippa J. Talmud, Steve E. Humphries, John Whittaker, Richard W. Morris, Peter H. Whincup, Anna Dominiczak, Patricia B. Munroe, Toby Johnson, Alison H. GoodallFrancois Cambien, Patrick Diemert, Christian Hengstenberg, Willem H. Ouwehand, Janine F. Felix, Nicole L. Glazer, Maciej Tomaszewski, Paul R. Burton, Martin D. Tobin, Dirk J. van Veldhuisen, Rudolf A. de Boer, Gerjan Navis, Wiek H. van Gilst, Bongani M. Mayosi, John R. Thompson, Meena Kumari, Peter W. MacFarlane, Ian N. M. Day, Aroon D. Hingorani, Nilesh J. Samani*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)

Abstract

Background-Presence of left ventricular hypertrophy on an ECG (ECG-LVH) is widely assessed clinically and provides prognostic information in some settings. There is evidence for significant heritability of ECG-LVH. We conducted a large-scale gene-centric association analysis of 4 commonly measured indices of ECG-LVH.

Methods and Results-We calculated the Sokolow-Lyon index, Cornell product, 12-lead QRS voltage sum, and 12-lead QRS voltage product in 10 256 individuals from 3 population-based cohorts and typed their DNA using a customized gene array (the Illumina HumanCVD BeadChip 50K array), containing 49 094 genetic variants in approximate to 2100 genes of cardiovascular relevance. We followed-up promising associations in 11 777 additional individuals. We identified and replicated 4 loci associated with ECG-LVH indices: 3p22.2 (SCN5A, rs6797133, P=1.22X10(-7)) with Cornell product and 12q13.3 (PTGES3, rs2290893, P=3.74X10(-8)), 15q25.2 (NMB, rs2292462, P=3.23X10(-9)), and 15q26.3 (IGF1R, rs4966014, P=1.26X10(-7)) with the 12-lead QRS voltage sum. The odds ratio of being in the top decile for the 12-lead QRS voltage sum for those carrying 6 trait-raising alleles at the 12q13.3, 15q25.2, and 15q26.3 loci versus those carrying 0 to 1 alleles was 1.60 (95% CI: 1.20 to 2.29). Lead single-nucleotide polymorphisms at the 12q13.3 and 15q25.2 loci showed significant expression quantitative trait loci effects in monocytes.

Conclusions-These findings provide novel insights into the genetic determination of ECG-LVH. The findings could help to improve our understanding of the mechanisms determining this prognostically important trait. (Circ Cardiovasc Genet. 2011;4:626-635.)

Original languageEnglish
Pages (from-to)626-U314
Number of pages31
JournalCirculation-Cardiovascular Genetics
Volume4
Issue number6
DOIs
Publication statusPublished - Dec-2011

Keywords

  • electrocardiography
  • left ventricular hypertrophy
  • genetics
  • genetic variation
  • association study
  • GENOME-WIDE ASSOCIATION
  • LINKAGE ANALYSIS
  • COMMON VARIANTS
  • BLOOD-PRESSURE
  • CARDIOMYOPATHY
  • HYPERTENSION
  • DURATION
  • HEART
  • IDENTIFICATION
  • METAANALYSIS

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