title: Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease.
abstract: Data from both experimental models and humans provide evidence that ghrelin and its receptor, the growth hormone secretagogue receptor (ghrelin receptor, GHSR), possess a variety of cardiovascular effects. Thus, we hypothesized that genetic variants within the ghrelin system (ligand ghrelin and its receptor GHSR) are associated with susceptibility to myocardial infarction (MI) and coronary artery disease (CAD). Seven single nucleotide polymorphisms (SNPs) covering the GHSR region as well as eight SNPs across the ghrelin gene (GHRL) region were genotyped in index MI patients (864 Caucasians, 'index MI cases') from the German MI family study and in matched controls without evidence of CAD (864 Caucasians, 'controls', MONICA Augsburg). In addition, siblings of these MI patients with documented severe CAD (826 'affected sibs') were matched likewise with controls (n = 826 Caucasian 'controls') and used for verification. The effect of interactions between genetic variants of both genes of the ghrelin system was explored by conditional classification tree models. We found association of several GHSR SNPs with MI [best SNP odds ratio (OR) 1.7 (1.2-2.5); P = 0.002] using a recessive model. Moreover, we identified a common GHSR haplotype which significantly increases the risk for MI [multivariate adjusted OR for homozygous carriers 1.6 (1.1-2.5) and CAD OR 1.6 (1.1-2.5)]. In contrast, no relationship between genetic variants and the disease could be revealed for GHRL. However, the increase in MI/CAD frequency related to the susceptible GHSR haplotype was abolished when it coincided with a common GHRL haplotype. Multivariate adjustments as well as permutation-based methods conveyed the same results. These data are the first to demonstrate an association of SNPs and haplotypes within important genes of the ghrelin system and the susceptibility to MI, whereas association with MI/CAD could be identified for genetic variants across GHSR, no relationship could be revealed for GHRL itself. However, we found an effect of GHRL dependent upon the presence of a common, MI and CAD susceptible haplotype of GHSR. Thus, our data suggest that specific haplotypes of the ghrelin ligand and its receptor act epistatically to affect susceptibility or tolerance to MI and/or CAD.
authors.affiliation: Clinic for Internal Medicine II, University of Regensburg Franz-Josef-Stauss Allee 11, 93053 Regensburg, Germany. andrea.baessler@klinik.uni-regensburg.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Baessler
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Bjoern
authors.initials: B
authors.lastname: Mayer
authors.forename: Martina
authors.initials: M
authors.lastname: Koehler
authors.forename: Silke
authors.initials: S
authors.lastname: Wiedmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.forename: Angela
authors.initials: A
authors.lastname: Doering
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Guenter
authors.initials: G
authors.lastname: Riegger
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics*; D003663:Decision Trees; D005260:Female; D020022:Genetic Predisposition to Disease; D054439:Ghrelin; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D036361:Peptide Hormones / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D054440:Receptors, Ghrelin; D035781:Siblings
chemical_list: D054439:Ghrelin; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin