Premature Myocardial Infarction Novel Susceptibility Locus on Chromosome 1P34-36 Identified by Genomewide Linkage Analysis

Qing Wang, Shaoqi Rao, Gong Qing Shen, Lin Li, David J. Moliterno, L. Kristin Newby, William J. Rogers, Ruth Cannata, Erich Zirzow, Robert C. Elston, Eric J. Topol

Research output: Contribution to journalArticlepeer-review

176 Scopus citations

Abstract

The most frequent causes of death and disability in the Western world are atherosclerotic coronary artery disease (CAD) and acute myocardial infarction (MI). This common disease is thought to have a polygenic basis with a complex interaction with environmental factors. Here, we report results of a genomewide search for susceptibility genes for MI in a well-characterized U.S. cohort consisting of 1,613 individuals in 428 multiplex families with familial premature CAD and MI: 712 with MI, 974 with CAD, and average age of onset of 44.4 ± 9.7 years. Genotyping was performed at the National Heart, Lung, and Blood Institute Mammalian Genotyping Facility through use of 408 markers that span the entire human genome every 10 cM. Linkage analysis was performed with the modified Haseman-Elston regression model through use of the SIBPAL program. Three genomewide scans were conducted: single-point, multipoint, and multipoint performed on of white pedigrees only (92% of the cohort). One novel significant susceptibility locus was detected for MI on chromosomal region 1p34-36, with a multipoint allele-sharing P value of <10-12 (LOD = 11.68). Validation by use of a permutation test yielded a pointwise empirical P value of .00011 at this locus, which corresponds to a genomewide significance of P < .05. For the less restrictive phenotype of CAD, no genetic locus was detected, suggesting that CAD and MI may not share all susceptibility genes. The present study thus identifies a novel genetic-susceptibility locus for MI and provides a framework for the ultimate cloning of a gene for the complex disease MI.

Original languageEnglish
Pages (from-to)262-271
Number of pages10
JournalAmerican Journal of Human Genetics
Volume74
Issue number2
DOIs
StatePublished - Feb 2004

Bibliographical note

Funding Information:
We thank J. Weber and the NHLBI Mammalian Genotyping Service, for genotyping; Edward Plow, from the Cleveland Clinic; JoAnne Meyer, Alex Parker, and Goeff Ginsburg, from Millennium, for their input; and other members of Wang Laboratory (S. Chen, A. Timur, C. Fan, S. You, L. Wu, M. Liu, R. Kadaba, and L. Wang), for preparing DNA samples for genotyping. This study was supported by the Cardiovascular Genetics Funds from the Cleveland Clinic Department of Cardiovascular Medicine, a Doris Duke Innovation in Clinical Research Award (to Q.W. and E.J.T.), and by U.S. Public Health Service resource grant RR03655 from the National Center for Research Resources and by research grant GM28356 from the National Institute of General Medicine Sciences (support to R.C.E.). Q.W. is also supported by National Institutes of Health grants R01 HL65630 and R01 HL66251. We thank the following participants in this study: Cleveland Clinic Foundation: David J. Moliterno, Gurunathan Murugesan, Patricia Welsh, and Monique Rosenthal; Emory University Hospital, Atlanta: Spencer B. King III, William Anderson, Joe Jean Borowski, and Kris Anderberg; Mayo Clinic, Rochester, MN: David R. Holmes, Jr., Charanjit Rihal, and Sharon McIntire-Langworthy; University of Alabama Medical Center, Birmingham: Ann Snider; Duke University Medical Center, Durham, NC: Laura Drew; the Lindner Center for Clinical Cardiovascular Research, Cincinnati: Dean Kereiakes, Eli Roth, and Louise Wohlford; LeBauer Cardiovascular Research Foundation, Greensboro, NC: Anthony De Franco and Teresa Schrader; St. Joseph Hospital, Savannah: Phillip Gainey and Sandra Arsenault; Lancaster Heart Foundation, Lancaster, PA: Paul Casale and Joann Tuzi; Latter Day Saints Hospital, Salt Lake City: Jeffrey Anderson, Juli Jerman, Rob Pearson, and Ann Allen; Diabetes and Glandular Associates, San Antonio: Sherwyn Schwartz and Sue Beasie; St. Louis University Hospital, St. Louis: Frank Aguirre, Sandra Aubuchon, and Kristin Weisbrod; the Heart Group, Saginaw: Jeffrey Carney and Muriel Harris; Michigan Heart and Vascular Institute, Ypsilanti: Jim Bengtson and Mary Adolphson; Oregon Cardiology Clinic, Portland: John Rudoff and Sue Williams.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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