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Polymorphisms in 33 inflammatory genes and risk of myocardial infarction—a system genetics approach

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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.

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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

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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.”

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Correspondence to François Cambien.

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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

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  • DOI: https://doi.org/10.1007/s00109-007-0234-x

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