Abstract
The hypothesis of a causal link between inflammation and atherosclerosis would be strengthened if variants of inflammatory genes were associated with disease. Polymorphisms of 33 genes encoding inflammatory molecules were tested for association with myocardial infarction (MI). Patients with MI and a parental history of MI (n = 312) and controls from the UK (n = 317) were genotyped for 162 polymorphisms. Thirteen polymorphisms were associated with MI (P values ranging from 0.003 to 0.041). For three genes, ITGB1, SELP, and TNFRSF1B haplotype frequencies differed between patients and controls (P values < 0.01). We further assessed the simultaneous contribution of all polymorphisms and relevant covariates to MI using a two-step strategy of data mining relying on Random Forest and DICE algorithms. In a replication study involving two independent samples from the UK (n = 649) and France (n = 706), one interaction between the ITGA4/R898Q polymorphism and current smoking status was replicated. This study illustrates a strategy for assessing the joint effect of a large number of polymorphisms on a phenotype that may provide information that single locus or single gene analysis may fail to uncover. Overall, there was weak evidence for an implication of inflammatory polymorphisms on susceptibility to MI.
Similar content being viewed by others
Abbreviations
- ASO:
-
allele-specific oligonucleotide
- CHD:
-
coronary heart disease
- DICE:
-
Detection of Informative Combined Effects
- ECTIM:
-
Etude Cas-Témoins de l’Infarctus du Myocarde
- MI:
-
myocardial infarction
- FDR:
-
false-discovery rate
- GWA:
-
genome-wide association
- LD:
-
linkage disequilibrium
- MAF:
-
minor allele frequency
- MONICA:
-
multinational monitoring of trends and determinants in cardiovascular disease
- OMIM:
-
online mendelian inheritance in man
- RF:
-
Random Forest
- SEM:
-
stochastic version of the expectation-maximisation algorithm
- SSCP:
-
single strand conformation polymorphism
- THESIAS:
-
Testing Haplotype Effects In Association Studies
References
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352:1685–1695
Osterud B, Bjorklid E (2003) Role of monocytes in atherogenesis. Physiol Rev 83:1069–1112
Fichtlscherer S, Heeschen C, Zeiher AM (2004) Inflammatory markers and coronary artery disease. Curr Opin Pharmacol 4:124–131
Cambien F (2005) Coronary heart disease and polymorphisms in genes affecting lipid metabolism and inflammation. Curr Atheroscler Rep 7:188–195
Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy P, Luc G, et al (1992) A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease. The ECTIM Study. Arterioscler Thromb 12:701–707
Herrmann SM, Ricard S, Nicaud V, Brand E, Behague I, Blanc H, Ruidavets JB, Evans A, Arveiler D, Luc G, Poirier O, Cambien F (2000) Polymorphisms in the genes encoding platelet-derived growth factor A and alpha receptor. J Mol Med 78:287–292
Kee F, Morrison C, Evans AE, McCrum E, McMaster D, Dallongeville J, Nicaud V, Poirier O, Cambien F (2000) Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study. Etude cas-temoin de l’infarctus myocarde. Heart 84:548–552
Cambien F, Poirier O, Nicaud V, Herrmann SM, Mallet C, Ricard S, Behague I, Hallet V, Blanc H, Loukaci V, Thillet J, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L (1999) Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet 65:183–191
Tregouet DA, Escolano S, Tiret L, Mallet A, Golmard JL (2004) A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm. Ann Hum Genet 68:165–177
Tregouet DA, Barbaux S, Escolano S, Tahri N, Golmard JL, Tiret L, Cambien F (2002) Specific haplotypes of the P-selectin gene are associated with myocardial infarction. Hum Mol Genet 11:2015–2023
Pounds S, Cheng C (2006) Robust estimation of the false discovery rate. Bioinformatics 15:15
Breiman L, Friedman J (1984) Classification and regression trees. Wadsworth and Brooks, Monterey, CA
Breiman L (2001) Random Forests. Machine Learning 45:5–32
Lunetta KL, Hayward LB, Segal J, Van Eerdewegh P (2004) Screening large-scale association study data: exploiting interactions using random forests. BMC Genet 5:32
Bureau A, Dupuis J, Falls K, Lunetta KL, Hayward B, Keith TP, Van Eerdewegh P (2005) Identifying SNPs predictive of phenotype using random forests. Genet Epidemiol 28:171–182
Tahri-Daizadeh N, Tregouet DA, Nicaud V, Manuel N, Cambien F, Tiret L (2003) Automated detection of informative combined effects in genetic association studies of complex traits. Genome Res 13:1952–1960
Oda K, Tanaka N, Arai T, Araki J, Song Y, Zhang L, Kuchiba A, Hosoi T, Shirasawa T, Muramatsu M, Sawabe M (2007) Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Hum Mol Genet 16:592–599
Cambien F, Tiret L (2005) Atherosclerosis: from genetic polymorphisms to system genetics. Cardiovasc Toxicol 5:143–152
Ghazalpour A, Doss S, Yang X, Aten J, Toomey EM, Van Nas A, Wang S, Drake TA, Lusis AJ (2004) Thematic review series: the pathogenesis of atherosclerosis. Toward a biological network for atherosclerosis. J Lipid Res 45:1793–1805
GO (2006) The gene ontology (GO) project in 2006. Nucleic Acids Res 34:D322–326
Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC (2006) A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 31:31
Thomas DC, Haile RW, Duggan D (2005) Recent developments in genomewide association scans: a workshop summary and review. Am J Hum Genet 77:337–345
Tahri-Daizadeh N, Tregouet DA, Nicaud V, Poirier O, Cambien F, Tiret L (2004) Exploration of multilocus effects in a highly polymorphic gene, the apolipoprotein (APOB) gene, in relation to plasma apoB levels. Ann Hum Genet 68:405–418
Rohde LE, Lee RT (2003) Pathophysiology of atherosclerotic plaque development and rupture: an overview. Semin Vasc Med 3:347–354
Schafers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schafers KP, Law MP, Schober O, Levkau B (2004) Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 109:2554–2559
Acknowledgments
We deeply thank Stanley Pounds for his assistance and fruitful discussions on multiple testing issues. INSERM UMR S 525 was supported by grants from the French Ministry of Research (ACI IMPBIO No. 032619) and Fondation de France No. 2002004994; C. Combadiere was supported by Fondation de France No. 2003 005634; S.M. Brand-Herrmann was supported in part by a research grant from the Bundesministerium for Education, Science and Technology in the context of the BioProfile-Project “Innovations in treatment concepts for the metabolic syndrome” (BMBF 0313040C) and participant in the grant of the Deutsche Forschungsgemeinschaft: “Graduierten-Kolleg 754, Myokardiale Genexpression und Funktion, Myokardhypertrophie.”
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Barbaux, S., Tregouet, DA., Nicaud, V. et al. Polymorphisms in 33 inflammatory genes and risk of myocardial infarction—a system genetics approach. J Mol Med 85, 1271–1280 (2007). https://doi.org/10.1007/s00109-007-0234-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-007-0234-x