title: Premature myocardial infarction novel susceptibility locus on chromosome 1P34-36 identified by genomewide linkage analysis.
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.
authors.affiliation: Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Lerner Research Institute, The Cleveland Clinic Foundation, OH 44195, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Shaoqi
authors.initials: S
authors.lastname: Rao
authors.forename: Gong-Qing
authors.initials: GQ
authors.lastname: Shen
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: David J
authors.initials: DJ
authors.lastname: Moliterno
authors.forename: L Kristin
authors.initials: LK
authors.lastname: Newby
authors.forename: William J
authors.initials: WJ
authors.lastname: Rogers
authors.forename: Ruth
authors.initials: R
authors.lastname: Cannata
authors.forename: Erich
authors.initials: E
authors.lastname: Zirzow
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000328:Adult; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*