The multiple pathogenetic pathways leading to AMI include genetic heterogeneity or multiple genetic traits associated with the disease. Recent genome-wide association (GWA) studies have contributed substantially to the discovery of new SNPs associated with CHD and AMI , but their clinical relevance is still unclear because a single gene variant can make a limited contribution to the total genetic load of AMI, and both common and rare gene polymorphisms may differentially affect susceptibility to the disease. These factors may also partially explain the contradictory results of genetic association studies using the candidate gene approach in AMI case/control studies [24–26].
It is important to know that subjects with an affected parent have a two-fold greater risk of CHD than those without a family history [13–15]. Genetic studies of the children of parents with CVD have shown that genetic variations in the promoter region of the APOA1 gene are associated with differences in serum ApoA1 and HDL levels in healthy subjects, and that this effect is influenced by gender and a family history of AMI . A parental history of hypertension is a risk factor for high blood pressure among Offs, whose blood pressure is partially affected by variations (deletions/insertions) in the angiotensin converting enzyme . Hyper-homocysteinemia is frequent in homozygotes for the C677T polymorphism of the MTHFR gene and associated with an increased risk of CHD in children with a positive family history . It has also been found that the same SNP is associated with congenital atrial septal defects, and that these heart alterations are more frequent in the children from mothers carrying the MTHFR TT genotype .
It is known that a family history and a still largely undefined genetic background greatly influence the early clinical manifestation of AMI and CVD. Therefore, we investigated SNPs in genes with a regulatory effect on inflammatory responses as possible genetic markers of an increased risk of CVD in children of parents with a positive history of AMI. It is interesting that 45% of the Offs in our investigation had a father who suffered an AMI before he reached the age of 56 years.
We chose elderly CTR from a longitudinal population study because they did not have a history of CVD, and did not experience an AMI or have any other CVD before and during the five years of follow-up. A second control group of comparable age from the WHO-MONICA-Brianza study to compare the CVE prevalence during the 24 years follow-up of our Offs was also used. The control disease consisted of patients with clinical sporadic AMI.
SNPs in the VEGF, IL-10 and IFN-γ genes were differently distributed in Offs and CTR, and it is interesting to note that the genetic make-up of the Offs overlapped that of the unrelated population of patients with a clinical diagnosis of sporadic AMI (control disease).
It has been suggested that the CC genotype of the VEGF gene, together with two other SNPs in the promoter region of this gene, increases VEGF gene expression in human myoblasts  and the production of the cognate protein in human peripheral blood lymphocytes activated by lipopolisaccaride . Subjects with the VEGF CC genotype may produce increased levels of VEGF protein which, by deregulating angiogenesis, may lead to an increased risk of CVE.
The published data regarding the functional relevance of IL-10 SNPs are conflicting. An initial study found that the IL-10 A allele is associated with a two-fold increase in transcriptional activity in B cell lines , but it has been subsequently reported that the A allele is associated with a reduction in the IL-10 secretion of activated peripheral blood lymphocytes [34–36]. These data support the hypothesis that the suppression of inflammation may be impaired in carriers of the −1082 A allele in the IL-10 gene. These findings suggest that impaired regulation of inflammatory responses in Offs with one or two copies of the IL-10 A allele may increase the risk of CVE.
The +874 A allele of the IFN-γ gene decreases the production of the cognate protein and resistance to tuberculosis infection . Our findings showing an increased frequency of the +874 A allele in Offs are in accordance with another study reporting that patients with the +874 AA genotype and idiopathic dilated cardiomyopathy showed a worse prognosis and an adverse outcome . Furthermore, patients with dilated cardiomyopathy showed an impaired activation of CD4T cells by IFN-γ ascribed to a decreased production of this cytokine . These findings suggest that a decreased release of IFN-γ may negatively affect the coordination of immune responses in vessel walls, accelerate atherogenesis, and increase the risk of CVE in Offs with the IFN-γ A allele.
The concomitant presence of the CC genotype of the VEGF gene, the A allele of the IL-10 gene, and the A allele of the IFN-γ gene was more frequent in our AMI group, and significantly increased the risk of the disease. It is interesting to note that this triple genotype profile was found in 46% of Offs and led to a presumptive high risk of CVE (OR = 4.129). This observation supports the notion that Offs with a positive parental history are at high risk of CVE and the pro-inflammatory genetic signature may be part of the complex genetic background influencing AMI risk.
The increased risk of CVE predicted by genetic signature was partially confirmed by the 24-year follow-up, which clearly revealed a significant increase in CVE in Offs. Furthermore, gender and age are also strong risk factors, as CVE increased prevalence was only observed in older male Offs (Table 8). The type of relationship between the presence of the triple genotype and CVE manifestation could not be assessed, since the limited number of Offs positive for CVE. Further follow up of these subjects may clarify this topic.
BMI from Offs was slightly increased when compared with the ideal age value and CTR selected for this investigation showed an increased BMI as expected since their advanced age. Cholesterol blood profile data from Offs group were in the normal range for their age cohort. Among Offs only 33 subjects used for limited time periods statins and the number of statins users was further reduced when it was stratified between triple genotype carriers and non carriers. Therefore, statins use showed very limited influence upon the lipid profile data from Offs population. Furthermore, since the presence of the triple genotype/allele signature did not affect BMI or the blood levels of total cholesterol, HDL, LDL or triglycerides, we suggest that it might affect the incidence of CVE by mechanisms that are partially independent of those affected by the classic risk factors of CVD.