Published online before print August 12, 2004, doi: 10.1161/01.STR.0000140740.19421.fe
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(Stroke. 2004;35:2270.)
© 2004 American Heart Association, Inc.
Original Contributions |
Proinflammatory Genetic Profiles in Subjects With History of Ischemic Stroke
From the Laboratory of Vascular Biology and Genetics (A.F., E.G., P.Papaleo, G.S., A.S.P., G.P., P.Pola, R.P.) and the Department of Medicine (A.F., E.G., P.Papaleo, G.S., A.S.P., G.P., P.T., P.Pola, R.P.), A. Gemelli University Hospital, Università Cattolica del Sacro Cuore, School of Medicine, Rome, Italy.
Correspondence to Dr Roberto Pola, Instituto di Patologia Speciale Medica, Università Cattolica del Sacro Cuore, A. Gemelli University Hospital, L.go A. Gemelli 8, 00168 Rome, Italy. E-mail rob_pola{at}hotmail.com
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Abstract |
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Background and Purpose— Proinflammatory genetic profiles, resulting from the combination of single nucleotide polymorphisms in genes encoding inflammatory molecules, may contribute to the development and progression of cardiovascular diseases. We evaluated the association between history of ischemic stroke and genetic profiles determined by the synergistic effects of polymorphisms in genes encoding prototypical inflammatory proteins.
Methods— The study included 237 individuals with history of ischemic stroke and 223 age-matched and gender-matched controls. The polymorphisms of the C-reactive protein (CRP), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-sel), and matrix metalloproteinase-3 (MMP-3) genes were studied.
Results— IL-6 GG, IL-6 GC, MCP-1 GG, ICAM-1 EE, E-sel AA, and MMP-3 5A5A genotypes were significantly and independently associated with stroke history. The odds of stroke increased with the number of high-risk genotypes: carrying 1 proinflammatory gene variant conferred a risk of 3.3 (1.6 to 6.9), whereas individuals concomitantly carrying 2 and 3 proinflammatory gene variants had adjusted odds ratios of 21.0 (7.6 to 57.5) and 50.3 (10.2 to 248.1), respectively.
Conclusions— Proinflammatory genetic profiles are significantly more common in subjects with stroke history. Synergistic effects between proinflammatory genotypes might be potential markers for cerebrovascular diseases.
Key Words: genetics • inflammation • stroke
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Introduction |
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In recent years, there has been increasing appreciation of the fact that inflammatory molecules, as well as single nucleotide polymorphisms of genes encoding inflammatory mediators, may contribute to the development and progression of a large number of pathological conditions, including cardiovascular diseases.1–9 Single nucleotide polymorphisms of proinflammatory and antiinflammatory genes may strongly influence the plasma levels and biological activity of the corresponding proteins,10–15 with potentially important clinical implications.
More recently, it has been suggested that proinflammatory gene variations may act synergistically and determine genetic profiles associated with increased risk for diseases, such as type 1 diabetes mellitus, gastric carcinoma, chronic atrophic gastritis, and rheumatoid arthritis.16–19 These findings have pointed out that the genetic susceptibility to specific diseases may be better identified by considering several genetic variants together.
In this study, we investigated the association between history of ischemic stroke and polymorphisms of genes encoding prototypical inflammatory molecules, such as C-reactive protein (CRP), interleukin-6 (IL-6), macrophage migration inhibitory factor (MIF), intercellular adhesion molecule-1 (ICAM-1), E-selectin (E-sel), macrophage chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-3 (MMP-3). Then, we evaluated whether the combined effects of these gene variations influenced the risk for stroke. Finally, we looked for proinflammatory genetic profiles that are associated with increased risk of stroke.
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Patients and Methods |
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Patients and controls were recruited among subjects consecutively admitted to the Department of Medicine of the A. Gemelli University Hospital of Rome, Italy, from January 1, 2001, to December 31, 2003. Subjects who had an ischemic stroke in the past and had survived this event were enlisted in the group of patients with history of ischemic stroke. The cerebral ischemic event had been documented by computerized tomography scan or magnetic resonance imaging of the brain. Among these individuals (n=395), those with history of cranial trauma, cerebral hemorrhage, atrial fibrillation, other major sources of cardioembolism, coagulation disorders, tumors, chronic inflammatory diseases, and autoimmune diseases were excluded from the study. After exclusion of these cases, a final number of 237 subjects was enrolled. Two hundred twenty-three individuals, attending the same Department of Medicine, matched for age and gender, and without clinical or radiological evidence of cerebrovascular disease were recruited as controls. The exclusion criteria were the same as those in the aforementioned patient group. Controls had no relationship with cases and no family history of stroke. All subjects were whites from central and southern Italy and belonged to independent pedigrees.
For all individuals enrolled in the study, a complete medical history was collected and included smoking habits, presence of diabetes, coronary artery disease, peripheral arterial occlusive disease, and drug treatment. Hypertension was defined as a systolic blood pressure >140 mm Hg, a diastolic blood pressure >90 mm Hg, or current treatment with an antihypertensive drug. Hypercholesterolemia was defined as either a need for hypolipidemic drugs or total plasma cholesterol level >5.18 mmol/L. Informed consent was obtained from all patients. The study protocol was accepted by the ethics committee of our university hospital.
Genetic Testing
DNA was extracted from peripheral blood and assayed, as previously described,8,20–24 for the detection of the following gene polymorphisms: CRP 1059 G/C, IL-6–174G/C, MIF–173G/C, ICAM-1–469E/K, E-sel Ser128Arg, MCP-1–2518A/G, and MMP-3–11715A/6A.
Statistical Analyses
Demographic and clinical data between groups were compared by 
2 test and by t test. Genotype and allele frequencies were compared by 2 test. Associations were calculated assuming a dominant or recessive relationship between the number of high-risk alleles and the prevalence of stroke history. Odds ratios were calculated with 95% confidence interval and in all cases were adjusted for age, sex, presence of hypertension, hypercholesterolemia, diabetes, coronary artery disease, peripheral arterial occlusive disease, and smoking. Statistical significance was established at P<0.05.
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Results |
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The demographic and clinical characteristics of stroke subjects and controls are summarized in Table 1.
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The distribution of the CRP, IL-6, MIF, MCP-1, ICAM-1, E-sel, and MMP-3 genotypes and alleles is shown in Table 2. Genotype frequencies in patients and controls did not deviate significantly from those expected under Hardy–Weinberg equilibrium. The frequency of the IL-6 GG genotype was significantly higher in patients with stroke history than in controls. A similar trend was observed for MCP-1 GG, ICAM-1 EE, MMP-3 5A5A, and E-sel AA genotypes. Likewise, the IL-6 G, MCP-1 G, ICAM-1 E, and E-sel A alleles were significantly more common in stroke patients than in controls.
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Then, we used a logistic regression model to evaluate whether these gene polymorphisms were independently associated with history of ischemic stroke (Table 3). The analyses were conducted assuming a recessive or a dominant relationship between the high-risk alleles and the presence of stroke history. Regarding the IL-6 gene polymorphism, we found that compared with the CC genotype, both the GG and the GC genotypes were significantly and independently associated with stroke history. For the other investigated polymorphisms, the odds for history of ischemic stroke was significantly increased only in subjects carrying 2 copies of the high-risk alleles.
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To assess the combined effect of these genotypes, patients and controls were stratified according to the number of high-risk proinflammatory genotypes (Table 4). Interestingly, the odds ratio for stroke history increased progressively with the number of high-risk genotypes carried by a given individual: it was 3.3 (1.6 to 6.9) in the group of subjects with 1 proinflammatory genotype, increased to 21.0 (7.6 to 57.5) in subjects with 2 high-risk genotypes, and peaked at 50.3 (10.2 to 248.1) in subjects concomitantly carrying 3 high-risk genotypes.
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Then, we investigated which genotypical combinations were more significantly associated with stroke history. Subjects exposed to 1, 2, and 3 proinflammatory gene polymorphisms were classified according to their genetic profile and compared with individuals with no high-risk gene variations (Table 5). This analysis showed that among subjects exposed to 1 high-risk genotype, only those carrying the G allele of the IL-6 G/C gene polymorphism (G+ individuals) had a significant and independent increased risk of stroke. Among subjects exposed to 2 high-risk genotypes, a significant and independent association with stroke history was found only in those carrying the IL-6 G allele in combination with the ICAM-1 EE, the E-sel AA, the MCP-1 GG, and the MMP-3 5A5A genotypes. In the case of subjects exposed to 3 high-risk genotypes, a significant and independent association with stroke history was found for the IL-6 G+/ICAM-1 EE+/MCP-1 GG+ and the IL-6 G+/ICAM-1 EE+/MMP-3 5A5A+ genetic profiles.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This study shows that IL-6, E-sel, ICAM-1, MCP-1, and MMP-3 gene polymorphisms are significantly and independently associated with stroke history. It also demonstrates that in subjects with stroke history, synergistic effects between these proinflammatory gene polymorphisms determine genetic profiles that are associated with different levels of risk for stroke history, depending on the number and type of high-risk genotypes concomitantly carried by a given individual.
The biological significance of the observed associations is based on the fact that the gene mutations investigated in this study are functionally important. Indeed, the –174G/C polymorphism of the IL-6 gene promoter influences the transcription rate of the gene and regulates IL-6 plasma concentrations.11 Similarly, the MCP-1–2518A/G polymorphism influences the expression of the MCP-1 gene.10,25 Also the –11715A/6A polymorphism of the MMP-3 gene promoter regulates transcription and protein levels in an allele-specific manner.26 However, the 469 E/K polymorphism of the ICAM-1 gene results in a change in the amino acid sequence of the Ig-like domain 5, which is crucial for the interactions between ICAM-1 and LFA-1 and for the adhesion of B-cells.27 Likewise, the E-sel Ser128Arg gene polymorphism can functionally alter leukocyte–endothelial interactions.15 These important biological effects have, not surprisingly, relevant clinical consequences, as indicated by the influence that these gene polymorphisms may exert on the onset and severity of several clinical pathologic conditions, including cardiovascular diseases.28–32
Our findings are consistent with the concept that the individual overall chances of a specific inflammation-related disease developing might be affected by a susceptibility profile that reflects the combined influence of multiple high-risk alleles.17,19 We found that the risk for stroke increases according to the number of inflammation-promoting genotypes carried by a given individual, suggesting that the gene mutations investigated in this study might act in a synergistic and cumulative manner. We also found that some genotypical combinations are more strongly associated with stroke history than others. In particular, carrying the IL-6 G allele, alone or in different combinations with the ICAM-1 EE, E-sel AA, MCP-1 GG, and MMP-35A5A genotypes, is strongly and consistently associated with stroke history. It is important to note that the synergistic and interdependent effects of these gene polymorphisms are mirrored by the important physiological interactions that their corresponding proteins display in vitro. MCP-1 is able to stimulate IL-6 secretion, and ICAM-1 synthesis is stimulated by MCP-1 in a time-dependent and dose-dependent manner.33,34 However, ICAM-1 induces expression of several proinflammatory cytokines, including IL-6, that in turn induce the synthesis of several acute phase proteins, thus promoting and maintaining the inflammatory phenotype.34,35
This study has some potential limitations. It is a case–control study, and recruitment and survival bias cannot be excluded. We studied a selected sample of patients admitted to a Department of Medicine for reasons not necessarily related to cerebral ischemia, and this population might not be representative of all patient groups. In addition, our population includes subjects with other cardiovascular diseases, and comorbidity might represent a confounding factor. The size of the studied population is relatively small and our findings need to be confirmed in larger samples and should be tested in groups of different ethnic origin. Some of the genes investigated in this study present >1 single nucleotide polymorphisms and it might be interesting to evaluate whether proinflammatory genetic haplotypes play a role in subjects with history of ischemic stroke. Finally, we cannot exclude that the observed associations depend on the effect of genes in linkage disequilibrium with the genes investigated in this study.
In conclusion, this study indicates that variations of genes encoding for prototypical inflammatory molecules, such as IL-6, ICAM-1, MCP-1, E-sel, and MMP-3, are significantly and independently associated with history of ischemic stroke. Synergistic effects between these gene polymorphisms determine proinflammatory genetic profiles that significantly influence the risk for stroke, which increases accordingly with the number of high-risk genotypes simultaneously carried by a given individual. Synergistic effects between proinflammatory genotypes might merit further investigation as potential markers of individual risk in cerebrovascular diseases.
Received May 13, 2004; revision received June 10, 2004; accepted July 5, 2004.
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