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Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P

Eur J Clin Invest 2011; 41 (12): 1330–1338 Abstract Background We hypothesized that, besides type 2 diabetes (T2D) and body mass index (BMI), circulating adiponectin concentration would be associated with variants of the ADIPOQ gene in patients with chronic heart failure (CHF). We also assessed the influence of these confounders on the prognostic value of adiponectin. Methods Plasma adiponectin was measured at entry and after 3 months in approximately 1200 patients with CHF enrolled in the GISSI-HF trial. Four common single-nucleotide polymorphisms (SNPs) spanning the ADIPOQ gene were studied: rs17300539 (−11391GA), rs266729 (−11377CG), rs2241766 (+45TG) and rs1501299 (+276GT). Associations with clinical characteristics and mortality were evaluated in patients with or without T2D. Results Adiponectin concentrations were negatively related to BMI, higher in women and older persons, but lower in patients with diabetes. T-allele carriers for rs1501299 and A-allele carriers for rs17300539 had significantly elevated adiponectin concentrations. Irrespective of diabetes, baseline plasma adiponectin was independently associated with mortality (adjusted HR [95%CI] per 1 SD increase in adiponectin concentration = 1·24[1·12–1·37], P

Objectives: Adiponectin has insulin-sensitizing, anti-inflammatory and anti-atherogenic properties. There are few and controversial data on the role of ADIPOQ variants in heart failure (HF) pathogenesis. We planned this large association study to investigate the potential association of four selected ADIPOQ polymorphisms with HF in a population of Italian origin. Methods: We genotyped 1173 cases with symptomatic HF and 1136 controls for alleles rs17300539, rs266729, rs1501299 and rs2241766. Cases were patients enrolled in the GISSI-Heart Failure genetic sub-study, with a long-term follow up (median 3.9 years). Controls were blood donors with no history of diabetes or cardiovascular disease (CVD). Genotype and allele frequencies of the four single nucleotide polymorphisms (SNPs) were compared between the two groups. Results: Clinical characteristics were significantly different between HF patients and controls. No significant differences were reported in the allelic and genotypic distribution, with the exception of rs266729 G allele, which showed a significant association with an increased risk of HF [odds ratio (OR) = 1.26; 95% confidence interval (CI) = 1.07–1.48; p = 0.006). We divided the GISSI-HF population according to HF etiology (ischemic and nonischemic) and presence of diabetes. For rs266729 G allele, a significant association with HF was confirmed in both ischemic (OR = 1.29; 95% CI = 1.06–1.56; p = 0.009) and nonischemic patients (OR = 1.2; 95% CI = 1.02–1.42; p = 0.03) as well as in nondiabetic patients (OR = 1.25; 95% CI = 1.05–1.49; p = 0.012). rs2241766 G allele showed a significant reduction of risk of HF in nonischemic (OR = 0.77; 95% CI = 0.62–0.95; p = 0.02) and diabetic patients (OR = 0.62; 95% CI = 0.45–0.84; p = 0.0025). Conclusions: We confirm the association between rs266729 G allele and an increased risk of HF and between rs2241766 G allele and decreased risk of HF. Our study extends the knowledge on the influence of ADIPOQ variants on CVD.

PTX3 is a long pentraxin of the innate immune system produced by different cell types (mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells) at the inflammatory site. It appears to have a cardiovascular protective function by acting on the immune-inflammatory balance in the cardiovascular system. PTX3 plasma concentration is an independent predictor of mortality in patients with acute myocardial infarction (AMI) but the influence of PTX3 genetic variants on PTX3 plasma concentration has been investigated very little and there is no information on the association between PTX3 variations and AMI. Subjects of European origin (3245, 1751 AMI survivors and 1494 controls) were genotyped for three common PTX3 polymorphisms (SNPs) (rs2305619, rs3816527, rs1840680). Genotype and allele frequencies of the three SNPs and the haplotype frequencies were compared for the two groups. None of the genotypes, alleles or haplotypes were significantly associated with the risk of AMI. However, analysis adjusted for age and sex indicated that the three PTX3 SNPs and the corresponding haplotypes were significantly associated with different PTX3 plasma levels. There was also a significant association between PTX3 plasma concentrations and the risk of all-cause mortality at three years in AMI patients (OR 1.10, 95% CI: 1.01-1.20, p = 0.02). Our study showed that PTX3 plasma levels are influenced by three PTX3 polymorphisms. Genetically determined high PTX3 levels do not influence the risk of AMI, suggesting that the PTX3 concentration itself is unlikely to be even a modest causal factor for AMI. Analysis also confirmed that PTX3 is a prognostic marker after AMI.

Objective: While many studies have shown an association between the gene coding for adiponectin (ADIPOQ) and adiponectin levels, much more controversy surrounds its association with metabolic traits such as insulin resistance, obesity and type 2 diabetes. Furthermore, very few studies have looked into the relations between ADIPOQ variants and risk of cardiovascular disease. The present study assessed the influence of four common ADIPOQ Single Nucleotide Polymorphisms (SNPs), rs17300539 (-11391G→A), rs266729 (-11377C→G), rs2241766 (+45T→G) and rs1501299 (+276G→T) on the risk of myocardial infarction and type 2 diabetes. Methods and Results: A large genetic association case-control study was conducted in 2008 Italians, including patients with myocardial infarction, type 2 diabetes, or both, and a reference group of healthy controls. Homozygotes TT for the rs1501299 (+276) had half the risk of either myocardial infarction alone or in association with type 2 diabetes when compared to the carriers of the G allele (OR = 0.58, p =0.01, and OR = 0.55, p =0.006 respectively). SNPs rs17300539 (-11391), rs266729 (-11377) and rs2241766 (+45) showed no significant association with any of the three case groups. Conclusions: These results suggest that homozygotes TT for the adiponectin polymorphism rs1501299 (+276) are protected from the risk of myocardial infarction.

Background A genomic region on chromosome 9p21 has been identified as closely associated with increased susceptibility to coronary artery disease (CAD) and to type 2 diabetes (T2D) although the evidence suggests that the genetic variants within chromosome 9p21 that contribute to CAD are different from those that contribute to T2D. We carried out an association case-control study in an Italian population to test the association between two single nucleotide polymorphisms (SNPs) on the 9p21 locus, rs2891168 and rs10811661, previously reported by the PROCARDIS study, and respectively myocardial infarction (MI) and T2D. Our aim was to confirm the previous findings on a larger sample and to verify the independence of their susceptibility effects: rs2891168 associated with MI but not with T2D and rs10811661 associated with T2D but not with MI. Methods Genomic DNA samples of 2407 Italians with T2D (602 patients), who had had a recent MI (600), or had both diseases (600) and healthy controls (605) were genotyped for the two SNPs. The genotypes were determined by allelic discrimination using a fluorescent-based TaqMan assay. Results SNP rs2891168 was associated with MI, but not with T2D and the G-allele odds ratio (OR) was 1.20 (95% CI 1.02-1.41); SNP rs10811661 was associated with T2D, but not with MI, and the T-allele OR was 1.27 (95% CI 1.04-1.55). ORs estimates from the present study and the PROCARDIS study were pooled and confirmed the previous findings, with greater precision. Conclusions Our replication study showed that rs2891168 and rs10811661 are independently associated respectively with MI and T2D in an Italian population. Pooling our results with those reported by the PROCARDIS group, we also obtained a significant result of association with diabetes for rs10811661 in the European population.

Summary. An improved method of isoelectric focusing (IEF) of haemoglobins, utilizing a spacer molecule to increase the separation between HbA and acetylated HbF, was carried out in parallel with carboxymethylcellulose (CMC) chromatography in 85 antenatal diagnoses for haemoglobinopathies (mainly thalassaemia). In 19 of 21 affected fetuses no HbA band was detectable on IEF while in two a very faint band was observed; in heterozygotes or normal fetuses a more obvious HbA band was present. Moreover, IEF was useful for the demonstration of HbLepore in two cases at risk for β-thalassaemia/HbLepore and for interpreting a radioactive pre-β globin peak on CMC chromatography. Pure fetal blood is needed for IEF. It can therefore be used for most cases in centres using fetoscopy for fetal blood sampling. About 80% of antenatal diagnosis of haemoglobinopathies may be carried out by IEF which is a very simple, rapid and inexpensive method.