Human Molecular Genetics Advance Access published online on February 26, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm033
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Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease
1 Clinic for Internal Medicine II, University of Regensburg, Regensburg, Germany 2 Clinic for Internal Medicine 2, University of Schleswig-Holstein, Luebeck, Germany 3 GSF Institute for Epidemiology, Neuherberg, Germany 4 Human & Molecular Genetics Center, Medical College of Wisconsin, USA
* Corresponding author: Andrea Baessler, M.D., Clinic for Internal Medicine II, Univeristy of Regensburg, Franz-Josef-Stauss Allee 11, 93053 Regensburg, Germany. Tel. +49 941 9447299; +49 941 9447211, Fax +49 941 9447338, andrea.baessler{at}klinik.uni-regensburg.de
Received January 14, 2007; Revised January 14, 2007; Accepted February 15, 2007
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).
Methods: Seven 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). Additionally, 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.
Results: 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 (OR1.6[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.
Conclusions: 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 suggests that specific haplotypes of the ghrelin ligand and its receptor act epistatically to affect susceptibility or tolerance to MI and/or CAD.
both authors contributed equally to this work
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