German Myocardial Infarction Research Articles

Association of Genetic Variation at AQP4 Locus with Vascular Depression.

Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression.

Lack of "obesity paradox" in patients presenting with ST-segment elevation myocardial infarction including cardiogenic shock: a multicenter German network registry analysis.

BackgroundStudies have associated obesity with better outcomes in comparison to non-obese patients after elective and emergency coronary revascularization. However, these findings might have been influenced by patient selection. Therefore we thought to look into the obesity paradox in a consecutive network STEMI population.MethodsThe database of two German myocardial infarction network registries were combined and data from a total of 890 consecutive patients admitted and treated for acute STEMI including cardiogenic shock and cardiopulmonary resuscitation according to standardized protocols were analyzed. Patients were categorized in normal weight (≤24.9 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2) according to BMI.ResultsBaseline clinical parameters revealed a higher comorbidity index for overweight and obese patients; 1-year follow-up comparison between varying groups revealed similar rates of all-cause death (9.1 % vs. 8.3 % vs. 6.2 %; p = 0.50), major adverse cardiac and cerebrovascular [MACCE (15.1 % vs. 13.4 % vs. 10.2 %; p = 0.53)] and target vessel revascularization in survivors [TVR (7.0 % vs. 5.0 % vs. 4.0 %; p = 0.47)] with normal weight when compared to overweight or obese patients. These results persisted after risk-adjustment for heterogeneous baseline characteristics of groups. An analysis of patients suffering from cardiogenic shock showed no impact of BMI on clinical endpoints.ConclusionOur data from two network systems in Germany revealed no evidence of an “obesity paradox”in an all-comer STEMI population including patients with cardiogenic shock.

Therapie des akuten ST-Streckenhebungs-Myokardinfarkts in Krankenhäusern mit und ohne Herzkatheterlabor

The goal of treatment of patients with ST-segment elevation acute myocardial infarction (STEMI) is to restore perfusion as soon as possible, preferably by primary percutaneous coronary intervention (PCI). The aim of this study of the German Myocardial Infarction Registry (DHR) was to document acute care and in-hospital course of STEMI patients in Germany. Over three months patients with STEMI were consecutively included and their basic data, treatments and in-hospital complications were centrally recorded using an internet-based standardized questionnaire. Included were 6,330 patients from 243 hospitals, in group 1 (primary admission in 136 hospitals with cath lab) 4,656 patients (74%) and in group 2 (primary admission in 107 hospitals without cath lab) 1,674 (26%). Reperfusion therapy was performed more frequently in patients of group 1 (91.1% PCI, 2.7% fibrinolysis) than in group 2 (80.7% PCI after transfer, 6.4% fibrinolysis). In-hospital mortality was 7.3% in all patients, 7.0% in group 1 and 8.3% in group 2. The DHR data show that about three quarters of patients with STEMI are primarily admitted to hospitals with cath labs. Primary PCI is the preferred treatment option both in hospitals with and without cath labs (in the latter after transfer); it is performed in about 85% of STEMI patients. In-hospital mortality is with over 7% higher in real-life than in randomized studies.

Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23

Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]. Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.

Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study

Background— Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed. Methods and Results— CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes &gt;22 000 cases with CAD, MI, or both and &gt;60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy ( P =2×10 −20 ). Conclusion— CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.

FGF21 signalling pathway and metabolic traits – genetic association analysis

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

Common Polymorphisms Influencing Serum Uric Acid Levels Contribute to Susceptibility to Gout, but Not to Coronary Artery Disease

BackgroundRecently, a large meta-analysis including over 28,000 participants identified nine different loci with association to serum uric acid (UA) levels. Since elevated serum UA levels potentially cause gout and are a possible risk factor for coronary artery disease (CAD) and myocardial infarction (MI), we performed two large case-control association analyses with participants from the German MI Family Study. In the first study, we assessed the association of the qualitative trait gout and ten single nucleotide polymorphisms (SNP) markers that showed association to UA serum levels. In the second study, the same genetic polymorphisms were analyzed for association with CAD.Methods and FindingsA total of 683 patients suffering from gout and 1,563 healthy controls from the German MI Family Study were genotyped. Nine SNPs were identified from a recently performed genome-wide meta-analysis on serum UA levels (rs12129861, rs780094, rs734553, rs2231142, rs742132, rs1183201, rs12356193, rs17300741 and rs505802). Additionally, the marker rs6855911 was included which has been associated with gout in our cohort in a previous study. SNPs rs734553 and rs6855911, located in SLC2A9, and SNP rs2231142, known to be a missense polymorphism in ABCG2, were associated with gout (p = 5.6*10−7, p = 1.1*10−7, and p = 1.3*10−3, respectively). Other SNPs in the genes PDZK1, GCKR, LRRC16A, SLC17A1-SLC17A3, SLC16A9, SLC22A11 and SLC22A12 failed the significance level. None of the ten markers were associated with risk to CAD in our study sample of 1,473 CAD cases and 1,241 CAD-free controls.ConclusionSNP markers in SLC2A9 and ABCG2 genes were found to be strongly associated with the phenotype gout. However, not all SNP markers influencing serum UA levels were also directly associated with the clinical manifestation of gout in our study sample. In addition, none of these SNPs showed association with the risk to CAD in the German MI Family Study.

Genetic determinants of circulating sphingolipid concentrations in European populations.

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.

Lack of Association Between a Common Polymorphism Near the INSIG2 Gene and BMI, Myocardial Infarction, and Cardiovascular Risk Factors

Epidemiological studies revealed an increasing prevalence of and a steep increase in obesity, a risk factor for cardiovascular disease. Because significant influence of a polymorphism, rs7566605, near the INSIG2 gene on BMI has been shown in the general population and in obesity cohorts, we hypothesized that this polymorphism might also act through an elevated BMI on the development of coronary artery disease (CAD) or myocardial infarction (MI). We pursued two strategies: First, the polymorphism rs7566605 was investigated for association with BMI, CAD/MI, and cardiovascular risk factors in a large German cohort at high risk for CAD and MI (n = 1,460 MI patients) as compared to unrelated healthy controls (n = 1,215); second, we extended our analyses on the families of MI patients and performed family-based association testing (n = 5,390 individuals). The polymorphism rs7566605 was analyzed using TaqMan technology. No deviation from Hardy-Weinberg equilibrium could be observed, and the call rate was 98.2%. No significant associations of rs7566605 with CAD/MI, BMI, and classical cardiovascular risk factors could be detected in the full sample size or in the subgroups. A total of 6,878 individuals were investigated in a population of German MI patients and their family members. Although the number of individuals was large enough, no influence of the rs7566605 INSIG2 polymorphism was detected on BMI and CAD/MI. We therefore conclude that in our sample the SNP rs7566605 near the INSIG2 gene does not influence BMI and is not associated directly with CAD/MI or indirectly through cardiovascular risk factors.

Association of three polymorphisms selected from a genome-wide association study with coronary heart disease in the Tunisian population

Despite extensive exploration of many genes, strong evidence of a molecular genetic association with coronary heart disease (CHD) or myocardial infarction (MI) remains to be obtained. Recently, significant interest has emerged in mapping genetic susceptibility for complex traits through whole-genome studies association generating promoting data that will determine the genetic contribution to common human diseases such as coronary heart disease. The aim of the present case-control study including 324 healthy controls and 296 patients with coronary heart disease from Tunisia, was to assess relation between three polymorphisms previously reported to be strongly associated with coronary heart disease in the Welcome Trust Case Control Consortium (WTCCC) and the German myocardial infarction family studies: locus 9p21.3 (rs 1333049), locus 6q25.1 (rs6922269) and 2q36.3 (rs2943634). By single locus analysis, no differences in genotype distribution and allelic frequency were found between the two groups of study. The risk allele (C) for rs2943634 was less frequent among Tunisian population than in controls from the WTCCC and German studies (57% vs 65%). The three SNPs previously reported to be associated with CHD were not replicated in our small sample.

Genetic variation in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is associated with myocardial infarction in the German population

Genetic variation in the genes ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) and stroke in Icelandic and Scottish populations. Both genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in a large study of German MI patients. Two previously described four SNP (single nucleotide polymorphism) haplotypes of the ALOX5AP gene (termed haplotype A and B) and one SNP (rs2660899) of the LTA4H gene conferring the greatest risk of MI in previous studies were genotyped in 1211 unrelated MI cases from the German MI Family Study and in 1015 healthy married-in spouses serving as controls. Haplotype B in the ALOX5AP gene was associated with an increased risk of MI in the German population, confirming previously reported associations of this haplotype with CAD (coronary artery disease) in populations from Scotland and Italy. No association with the risk of MI was detected for haplotype A of the ALOX5AP gene or for SNP rs2660899 representing the LTA4H gene. In conclusion, haplotype B of the ALOX5AP gene is associated with an increased risk of MI in a large German study. The present study is the third independent report from a European population describing an increased risk of CAD for carriers of haplotype B of the ALOX5AP gene, which substantiates further a role of this gene in the pathogenesis of CAD in Europeans.

Lack of association of genetic variants in the LRP8 gene with familial and sporadic myocardial infarction

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either.

Association of Common Polymorphisms in GLUT9 Gene with Gout but Not with Coronary Artery Disease in a Large Case-Control Study

BackgroundSerum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study.Methods and FindingsFirst, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52–0.75; p = 3.2*10−7). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region.ConclusionThus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population.

Abstract 3452: The Common Variant Rs9939609 In The FTO Gene Is Associated With Myocardial Infarction In Two Large German Populations (German Family MI Study And KORA-B)

Very recently, a genome-wide search for type 2 diabetes susceptibility genes identified a common variant in the FTO gene that predisposes to diabetes through an effect on body mass index (BMI). The A allele of rs9939609 (frequency 39%) was associated with increased BMI with a median per-allele change of ~0.36 kg/m2. Obesity (BMI &gt;30) is a major risk factor for cardiovascular disease, especially for myocardial infarction (MI). We aimed to identify the role of rs9939609 in two large German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. The first case group (Cases A) consists of 762 MI patients ascertained by a strong family history of MI. The second case group (Cases B) included 589 patients suffering from sporadic (non familial) MI from the German KORA register (KORA-B). The control group (Controls) consisted of participants of the WHO MONICA survey in Germany (n=1,644). The genotypes were either extracted from data of a genome wide scan using the 500K Affymetrix Gene Chip Array (Cases A and Controls) or by Taqman assay (Cases B). First, there was a non-significant trend towards higher BMI in carriers of the TA or AA genotype of rs9939609 in all populations under study (table 1 ). Second, rs9939609 was associated with MI in both MI populations (table 2 ). Our data suggest that rs9939609 within the FTO gene is related to the risk for MI in these two large German MI study samples. The function of FTO is mostly unknown. Hence, the mechanisms underlying the association between the FTO gene product and energy balance as well as the risks of diabetes and MI are unknown and require additional investigation. Table 1 Table 2

The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors

Recently, the genetic variant Y402H in the CFH (complement factor H) gene was associated with an increased risk for MI (myocardial infarction) in a prospective Caucasian cohort. In another nested case-control study, however, the CFH-Y402H variant did not carry susceptibility to MI. The aim of the present study was to test for an association between the CFH-Y402H variant and MI in a large case-control sample with a familial background for CAD (coronary artery disease). A total of 2161 individuals from the German MI family study were studied by questionnaire, physical examination and biochemical analyses. MI patients (n=1188; 51.4+/-8.6 years at first MI) were recruited from families with at least two members affected by MI and/or severe CAD. Spouses, sisters-in-law and brothers-in-law respectively, without MI/CAD were included as unaffected controls (n=973; 56.9+/-9.8 years). Genotyping was performed using a TaqMan assay. The common Y402H variant in the CFH gene was not associated with classical cardiovascular risk factors (diabetes, hypercholesterolaemia, hypertension, obesity, smoking and C-reactive protein serum levels). No association was found between the CFH-Y402H variant and susceptibility to MI. Separate analyses in both men and women revealed no gender-specific influence of the gene variant on cardiovascular risk factors or MI. This investigation was unable to replicate the association between the common CFH-Y402H variant and susceptibility to MI in our large Caucasian population which is enriched for genetic factors. We conclude that the CFH-Y402H variant has no relevant risk-modifying effect in our population.

Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations

Recent data provided strong evidence for the association of single nucleotide polymorphisms (SNPs) in the lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) genes with myocardial infarction (MI) in a Japanese population. For populations of other genetic background, the relevance of these polymorphisms in the pathogenesis of MI remains controversial. We aimed to define the role of LTA and LGALS2 SNPs in two German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. In the first population, MI patients were ascertained by a strong family history of MI (n = 1214). Controls were unrelated disease-free participants of the study (n = 1080). The second population included patients suffering from sporadic (nonfamilial) MI from the German KORA register (n = 607). The control group consisted of participants of the WHO MONICA survey in Germany (n = 1492). TaqMan assays were used to determine the genotypes of 4 SNPs in the LTA genomic region and 1 SNP in the LGALS2 gene. Single SNPs in both genomic regions as well as haplotypes in the LTA genomic region were tested for association in various models of inheritance. No association with MI could be found for any of the examined SNPs in the LTA genomic region and LGALS2 gene, or for haplotypes spanning the LTA genomic region. In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI. These variants are unlikely to play a significant role in populations of European origin.

Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease

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.

Common polymorphisms in the cannabinoid CB2 receptor gene (CNR2) are not associated with myocardial infarction and cardiovascular risk factors

Myocardial infarction (MI) is a complex disease. Multiple genes and their interaction with various environmental factors influence the pathogenesis of MI that is thought to be tightly regulated by inflammatory pathways. Recent progress in genetic analysis includes the use of large-scale genome-wide association studies that have proven to be powerful tools even in the analysis of multifactorial phenotypes. However, certain genes are only sparsely represented on the available gene chips and additional candidate gene approaches are necessary. One such example is the CNR2 gene, encoding the cannabinoid receptor 2 (CB2), which has been implicated in mediating anti-inflammatory and anti-atherosclerotic effects in vivo. We therefore hypothesized that genetic variations within the CNR2 gene are associated with the development of MI or classic cardiovascular risk factors. In a large case-control study, 1,968 individuals from the German MI family study were examined with 13 single nucleotide polymorphisms (SNPs) covering CNR2 and the adjacent genes. The association of these SNPs with MI or cardiovascular risk factors, such as arterial hypertension, obesity, hypercholesterolemia and diabetes mellitus, was determined. In allelic and genotypic models, none of the SNPs showed a significant association with MI. Separate analyses for men and women revealed no gender-specific relationship between common genetic variations within the CNR2 gene and MI. Moreover, no significant association between CNR2 gene variants and common cardiovascular risk factors was observed. We therefore provide evidence in a large German population that common polymorphisms within the CNR2 gene confer no susceptibility to MI or to cardiovascular risk factors.