(Circulation. 2000;101:e193.)
© 2000 American Heart Association, Inc.
Circulation Electronic Pages |
Possible Different Involvement of Interleukin-1 Receptor Antagonist Gene Polymorphism in Coronary Single Vessel Disease and Myocardial Infarction
"Angela Valenti" Laboratory of Genetic and Environmental Risk Factors for Thrombotic Disease, Department of Vascular Medicine and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
Fondazione Salvatore Maugeri Clinica del Lavoro e della Riabilitazione, IRCCS, Veruno, Italy
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To the Editor:
Francis et al1 recently reported that a polymorphism in the gene of the interleukin-1 receptor antagonist (IL-1Ra) is associated with the risk of single, but not multiple, vessel disease in a sample of Sheffield patients undergoing coronary angiography. The authors assume a true genetic distinction between the different expressions of vascular disease. However, a different pathogenetic involvement of the IL-1Ra gene in the mechanisms of atherosclerosis and thrombosis can also be suggested, with thrombosis being more frequent in the presence of multiple vessel disease. No data were, however, presented on patients with acute myocardial infarction (AMI).
We studied the IL-1RA gene in 158 Italian patients (129 men and 29 women) with AMI who were younger than 45 years (men) or 50 years (women) of age and who were frequency-matched for age and sex with 153 controls selected from a list of general practitioners in the same area. After amplification, 3 different alleles were identified: A1 (4 repeats) at 412 bp, A2 (2 repeats) at 240 bp, and A4 (5 repeats) at 498 bp.
Genotype distribution was in Hardy-Weinberg equilibrium
in cases and controls (
2=0.73,
P=0.3 and 2=0.85, P=0.3,
respectively). The frequency of alleles 1 and 2 in controls was
0.73 (95% confidence interval [CI], 0.67 to 0.68) and 0.25 (95% CI,
0.21 to 0.30), respectively, which is similar to the frequencies
described by Francis et al. The frequency of allele 4, which was
not found in the UK population, was lower (0.02; 95% CI, 0.01 to
0.04). The frequencies of the A1, A2, and A4 alleles in patients
were 0.72 (95% CI, 0.67 to 0.77), 0.25 (95% CI, 0.20 to 0.30) and
0.03 (95% CI, 0.01 to 0.05), respectively. Fisher’s exact test failed
to show any difference in either allelic frequency or genotype
distribution between patients and controls (P=0.81 and
P=0.89, respectively). Therefore, no association was
observed between IL-1Ra polymorphism and premature AMI.
Comparing these findings with those of Francis et al,1 it can be speculated that the activation of inflammation at a vascular site could be important for atherosclerosis development. Pathological studies, indeed, demonstrate that atherosclerotic lesions contain infiltrates of inflammatory cells and inflammatory components.2 Thrombus formation, a critical event in AMI, probably requires hemostasis activation,3 which might be only indirectly associated with inflammation.4
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1. Francis SE, Camp NJ, Dewberry RM, et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation. 1999;99:861–866.
2. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
3.
Iacoviello L, Di Castelnuovo A, De Knijff P, et
al. Polymorphisms in the coagulation factor VII gene and the risk
of myocardial infarction. N Engl J Med. 1998;338:79–85.
4. Rokita H, Neta R, Sipe JD. Increased fibrinogen synthesis in mice during the acute phase response: co-operative interaction of interleukin 1, interleukin 6, and interleukin 1 receptor antagonist. Cytokine. 1993;5:454–458. 9,2000[Medline] [Order article via Infotrieve]
Response
Divisions of Clinical Sciences and Molecular and Genetic Medicine, University of Sheffield, Sheffield, UK
Departments of Medical Genetics and Cardiological Sciences, St George’s Hospital Medical School, London, UK
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Dr Iacoviello and colleagues found no association of allele 2 of the interleukin-1 receptor antagonist (IL-1Ra) gene with premature myocardial infarction (MI) in a population of 158 Italian patients. In our study,R1 this allele was over-represented in angiographic, single-vessel coronary artery disease. This difference could arise for many reasons, including case definition (clearly true here), selective populations, relatively small samples, and population admixture, all of which are well-recognized problems with gene association studies.
The data presented by Iacoviello et al refer only to the
IL-1Ra genotype. The IL-1 cluster comprises 
3 functional
genes: IL-1
, IL-1ß, and IL-1Ra. A study of 8 markers across this
cluster found a strong degree of linkage disequilibrium within the
Northern English population, and several haplotypes could be
identified.R2 In this system, the biological outcome is,
therefore, determined by the interaction of the products of linked
genes. Thus, in our study, IL-1Ra may have been a marker of an IL-1
region haplotype that may not exist at the same frequency in the
Italian population. An individual polymorphism of a linkage group
may not reflect a genetic influence of the gene system in populations
as dissimilar as those of north and south Europe, especially when
clinical phenotypes are different.
Coronary atherosclerosis and MI are complex traits with important environmental influences. It is likely that heterogeneity in the genetic pathways may contribute to predisposition.
Different interpretations of our findings were discussed in our article. However, we still favor the continued testing of the hypothesis that the association we detected may represent a genetic risk conferred by the IL-1 gene family. Attempts to replicate this observation in independent populations are underway; some of them have shown an association between IL-1Ra polymorphisms and arterial disease.R3
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TopIntroductionReferencesIntroduction References |
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1. Francis SE, Camp NJ, Dewberry RM, et al. Interleukin-1 Receptor Antagonist Gene Polymorphism and Coronary Artery Disease. Circulation. 1999;99:861–866.
2. Cox A, Camp NJ, Nicklin MJH, et al. An analysis of linkage disequilibrium in the interleukin-1 gene cluster, using a novel grouping method for multiallelic markers. Am J Hum Genet.. 1998;62:1180–1088.[Medline] [Order article via Infotrieve]
3. Pankow JS, Beck JD, Offenbacher S, et al. Association of interleukin-1 gene variants and carotid arterial wall thickness: the ARIC study. Atherosclerosis. 1999;144(suppl 1):124. Abstract.
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