title: Expression pattern in human macrophages dependent on 9p21.3 coronary artery disease risk locus.
abstract: OBJECTIVE
  Genome-wide association studies identified a risk haplotype on chromosome 9p21.3 to be associated with coronary artery disease (CAD) and myocardial infarction (MI). Since this region does not contain a clear candidate gene with known pathophysiology, we performed a haplotype-specific expression study in human macrophages during pro-inflammatory stimulation to investigate the locus-dependent expression patterns in a model of atherosclerosis, the underlying cause for CAD and MI.
  
  
  METHODS
  Blood samples were taken from 40 male stable MI patients either homozygous for 9p21.3 risk (n = 20) or non-risk haplotype (n = 20) as well as from 28 healthy male individuals (n = 14 for each haplotype). Monocytes were isolated by density gradient centrifugation followed by differentiation into macrophages via M-CSF. Macrophages were either incubated with a pro-inflammatory IFNγ-LPS cocktail or kept untreated as controls. After 24 h, RNA was isolated and applied to Affymetrix Human Exon 1.0 ST Arrays.
  
  
  RESULTS
  Macrophages from MI patients and controls stratified for 9p21.3 haplotypes, exhibited marked differences in gene expression. Most pronounced differences were found in inflammatory mediators, like the chemokines CCL8 and CCL2 and the lectines CLEC4E and CLEC5A. Differences in expression changes could be seen most obviously during inflammatory stimulation for both, the interleukins IL12B and IL1B, and members of metallothionein gene family.
  
  
  CONCLUSIONS
  These findings show that gene expression is different in 9p21.3 haplotype-stratified macrophages. While these effects are relatively small in our in vitro model of atherosclerosis, these biological effects may contribute to a long term effect in risk haplotype carriers increasing susceptibility to CAD and MI.
authors: Department of Internal Medicine II, Regensburg University Medical Center, Regensburg, Germany. christa.zollbrecht@ukr.de
authors: Christa
authors: C
authors: Zollbrecht
authors: Martina
authors: M
authors: Grassl
authors: Sabine
authors: S
authors: Fenk
authors: Regina
authors: R
authors: Höcherl
authors: Ute
authors: U
authors: Hubauer
authors: Wibke
authors: W
authors: Reinhard
authors: Ulrike B
authors: UB
authors: Esslinger
authors: Stefanie
authors: S
authors: Ebert
authors: Thomas
authors: T
authors: Langmann
authors: Klaus
authors: K
authors: Stark
authors: Christian
authors: C
authors: Hengstenberg
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D016022:Case-Control Studies; D018925:Chemokines / Q000378:metabolism; D002899:Chromosomes, Human, Pair 9; D003324:Coronary Artery Disease / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007249:Inflammation; D007378:Interleukins / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D018925:Chemokines; D007378:Interleukins; D037181:Lectins, C-Type