Abstract 3191: Common SNPs and Haplotypes within the Growth Hormone Secretagogue Receptor Gene (GHSR, ghrelin receptor gene) are Associated with Myocardial Infarction
Genetic studies revealed a QTL on chr3q26 that has been linked to coronary artery disease (CAD) and obesity-associated phenotypes. This QTL harbors the ghrelin receptor gene, GHSR, which has been shown to play a role in obesity and might be involved in the tolerance or susceptibility of ischemic injury. GHSR is widely distributed in central and peripheral tissues, particularly in the cardiovascular system, and is up-regulated in atherosclerotic vessels. In fact, studies in experimental models and humans provide evidence that GHSR and its ligand ghrelin possess a variety of cardioprotective effects against myocardial ischemia, vasoactive and cardiotropic effects. Thus, we hypothesized that genetic variants within GHSR might be associated with differences in the susceptibility to myocardial infarction (MI). Methods: 10 SNPs covering the gene region were genotyped in index MI-patients (1429 Caucasians, “cases”) from the German MI family study and in an age- and sex stratified sample of the general population without evidence of CAD (MONICA Augsburg study, DNA of 1418 Caucasians, “controls”). Tests for associations were performed using individual SNPs and haplotypes derived from a high linkage disequilibrium (LD) block. MI was diagnosed using the WHO criteria and verified using hospital records. Results: LD analysis revealed a LD block consisting of 5 SNPs. We found association of the minor alleles of these 5 SNPs with MI using Armitage’s test for trend (best SNP OR 1.4 [1.1–1.9]). Moreover, we identified a common haplotype (frequency cases 29%, controls 26%, p=0.017) which significantly increases the risk for MI in the total study sample (OR=1.5 [1.1–2.0], p=0.006) as well as in men and women. The significance remained when performing 50.000 permutations (p=0.016). Multivariate adjustments for age, gender, BMI, blood pressure, and lipid levels revealed consistent results. Conclusion: To our knowledge, these data are the first to demonstrate an association of SNPs and haplotypes within the GHSR region and the susceptibility to MI. Multivariate adjustments indicate that these effects are independent of body mass. These results support the hypothesis that the GHSR/ghrelin system might play a role in the pathogenesis of atherosclerosis and MI.