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The Genomic Basis of Myocardial Infarction

Eric J. Topol, MD^_*,,_*

^_* Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio

View larger version (10K): [in a new window]   Figure 1 Single nucleotide polymorphisms (SNP), haplotypes (HAP), and microsatellites (MS).

View larger version (13K): [in a new window]   Figure 2 Progress in complex traits. SNP = single nucleotide polymorphism.

View larger version (73K): [in a new window]   Figure 3 (A) The thrombospondin (TSP)-4 mutation. Presence of mRNA and protein in endothelial cells, and abnormal calcium binding. (B) Effect of (P387)TSP-4 on proliferation of endothelial cells (EC). (C) Effect of TSP-4 variants and their fragments on adhesion of human umbilical vein endothelial cells. Cells were plated on plastic preincubated with purified TSP-4 variants (50,000 cells/well of 24-well plate), and photographs were taken after 24 h of culture (with permission from Stenina et al. [14]. mut = mutant(P387); vWF = von Willebrand factor; wt = wild type.

View larger version (30K): [in a new window]   Figure 4 Schematic of genome with 400 microsatellites evenly spaced for genome-wide scan markers.

View larger version (61K): [in a new window]   Figure 5 (A) Haseman-Elston sib-pair regression analysis for scanning loci segregating with myocardial infarction. The vertical axis of each plot is –log10(P) or pP, where the P is the significance level from each of two analyses. The solid line denotes the multipoint linkage profile for all pedigrees; the broken dotted/dashed line denotes the multipoint linkage profile for Caucasian-only pedigrees. The horizontal solid line in each subfigure indicates P = 2.2 x 10–5 (–log10(P) = 4.66 or logarithm of the odds ratio score = 3.6). The x axis denotes marker map positions. Note that the dashed line (p values for Caucasians only) is often not visible because it frequently overlaps with the solid line (p values for all study families). (B) Identification of a novel genetic linkage for myocardial infarction on chromosome 1p34-36. The vertical axis represents the –log10(P value) or pP, and the horizontal axis denotes the distance (cM) with markers along the chromosome. The results were obtained by multipoint linkage analysis of 2 cM intervals using the S.A.G.E. package (Statistical Analysis for Genetic Epidemiology, Statistical Solutions, Cork, Ireland). The asymptotic p values were quoted accurately to only 12 decimal places, resulting in a flat pP peak (with permission from Wang et al. [1]).

View larger version (79K): [in a new window]   Figure 6 (A) Genetic linkage of coronary artery disease (CAD)/myocardial infarction to chromosome 15q26 (adCAD1). Pedigree structure and genotypic analysis of kindred QW1576. Individuals with CAD are indicated by closed squares (men) or closed circles (women). Unaffected individuals are indicated by open symbols. Normal men under the age of 50 years or normal women less than 55 years are shown with light gray color as uncertain phenotype. Deceased individuals are indicated by a slash, "/." The proband is indicated by an arrow. Genotypes for markers D15S104, D15S212, D15S120, and D15S87 are shown below each symbol. Initial linage was identified with D15S120, which yielded a logarithm of the odds ratio score of 4.19 at a recombination fraction of 0. Haplotype cosegregating with the disease is indicated by a black vertical bar. (B) DNA sequence analysis of the wild-type (WT) allele and the 21-base pair (bp) deletion allele (21bp) of MEF2A. Sequence analysis of exon 11 of MEF2A in the proband (II.1) revealed the presence of a deletion. The WT and deletion alleles were separated by a 3% agarose gel and a single-strand conformation polymorphism (SSCP) gel, purified and sequenced directly. The location of 21bp is indicated. (C) 21bp results in a deletion of seven amino acids of MEF2A (Q440P441P442Q443P444Q445P446 or 7aa). (D) Functional characterization of WT and 7aa MEF2A proteins by transcriptional activation assays. The effect of 7aa on transcription activation activity of MEF2A was analyzed in the presence or absence of the zinc-finger transcription factor GATA-1 using the ANF–700 promoter. Transcriptional activity is shown as relative luciferase activity on the y axis. The transcriptional activity of the reporter gene only (vector) was set arbitrarily to 1. Western blot analysis with antiMEF2A rabbit polyclonal antiserum showed that both WT and mutant MEF2A (7aa) were successfully expressed in transfected HeLa cells (shown in the box; C, vector only as negative control; the MEF2A antibody detected two bands as previously reported). The data shown were from two independent experiments in triplicate, and are expressed as mean ± S.E. WT = wild type MEF2A; WT/7aa = coexpression of both wild type and mutant MEF2As; 7aa = the 7 amino acid deletion of MEF2A. (With permission from Wang et al. [36]).

View larger version (35K): [in a new window]   Figure 7 (A) Identification of MEFA2A mutation P279L in coronary artery disease (CAD) patient GB00305. (B) Structure of MEF2A protein with CAD/myocardial infarction-associated mutations indicated. The MEFA2A gene consists of 11 exons and encodes a 507 amino acid protein. The MCMI agamous deficiens serum response factor (MADS) domain and MEF2 domain at the N-terminal region are responsible for DNA binding, dimerization, and interaction with other transcription factor. The transcription activation domain is located in the middle portion, and the C-terminal region is responsible for nuclear localization site (NLS) (with permission from Bhagavatula et al. [37]).