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.
| Original language | English |
|---|---|
| Journal | Human Molecular Genetics |
| Volume | 16 |
| Issue number | 8 |
| Pages (from-to) | 887-899 |
| Number of pages | 13 |
| ISSN | 0964-6906 |
| DOIs | |
| Publication status | Published - 15.04.2007 |
Funding
This study was supported by Grants from the Deutsche Forschungsgemeinschaft (BA2227/1-1, He1921/9-1, Schu672/10-1, Schu672/12-1, Schu672/14-1, Ho1073/8-1), the Deutsche Akademie fuer Naturforscher Leopoldina (BMBF-LPD9901/8-72, MF), the German Federal Ministry for Research (KBF-FKZ 01GB9403, to Dr Schunkert), the National Genome Network (01GS0418 to Drs Schunkert and Hengstenberg), the Ernst-und Berta-Grimmke-Stiftung (Drs Hengstenberg and Schunkert), the Wilhelm-Vaillant-Stiftung (Drs Hengstenberg, Schunkert and Holmer), and the Deutsche Stiftung für Herzforschung (Drs Hengstenberg and Schun-kert), Germany. The KORA (Cooperative Research in the Region of Augsburg) research platform and the MONICA (Monitoring trends and determinants on cardiovascular diseases) Augsburg studies were initiated and financed by the GSF–National Research Centre for Environment and Health, which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. The MONICA Augsburg Study was initiated and conducted by Ulrich Keil and coworkers. KORA-gen was supported within the German National Genomic Research Network (NGFN) by the Federal Ministry of Education and Research (BMBF). We would like to thank all volunteers of the German MI family study and the MONICA Augsburg study for their participation. We also would like to acknowledge the excellent technical assistance of Josef Simon and Michaela Vöstner.
