Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project

Abstract

Background: Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD.

Methods: Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.

Results: We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.

Conclusion: Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.

Figure 1

Association of IL18R1 and IL18RAP SNPs with CVD risk in the whole MORGAM cohorts. Combined ORs [95% confidence interval] were obtained by use of the Mantel-Haenszel method and adjusted for age, gender and smoking status.

Figure 2

Pairwise Linkage Disequilibrium between the IL18R1 and IL18RAP SNPs. Pairwise Linkage Disequilibrium (LD) expressed in terms of r² and estimated in the whole MORGAM cohort using the Haploview software (Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21:263–265). The pattern of LD was homogeneous across the five European cohorts (data not shown).

Figure 3

Association between IL18R1 haplotypes and CVD risk in the whole MORGAM cohorts. Haplotypic ORs [95% confidence interval] adjusted for cohorts, age, gender and smoking habits are shown by comparison to the reference TTIGC haplotype. The global test of association was not significant (χ² = 7.231 with 7 df, p = 0.405). Polymorphisms are ordered according to their position on the genomic sequence.

Figure 4

Association between IL18RAP haplotypes and CVD risk in the whole MORGAM cohorts. Haplotypic ORs [95% confidence interval] adjusted for cohorts, age, gender and smoking habits are shown by comparison to the reference TAGTTA haplotype. The global test of association was not significant (χ² = 1.763 with 6 df, p = 0.940). Polymorphisms are ordered according to their position on the genomic sequence.

Figure 5

Association between IL18R1 haplotypes and CVD risk in the whole MORGAM cohorts according to smoking status. Haplotypic ORs [95% confidence interval] by comparison to the reference TTIGC haplotype were adjusted for cohorts, age, gender, separately in non-smokers (diamonds) and smokers (squares). The global tests of association were not significant (χ² = 4.796 with 6 df, p = 0.570 in non-smokers; χ² = 1.075 with 6 df, p = 0.983 in smokers). Polymorphisms are ordered according to their position on the genomic sequence.

Figure 6

Association between IL18RAP haplotypes and CVD risk in the whole MORGAM cohorts according to smoking status. Haplotypic ORs [95% confidence interval] by comparison to the reference TAGTTA haplotype were adjusted for cohorts, age, gender, separately in non-smokers (diamonds) and smokers (squares). The global tests of association were not significant (χ² = 2.639 with 6 df, p = 0.853 in non-smokers; χ² = 2.028 with 6 df, p = 0.917 in smokers). Polymorphisms are ordered according to their position on the genomic sequence.

Figure 7

Association between IL18R1 haplotypes and CVD risk in the whole MORGAM cohorts according to BMI. Haplotypic ORs [95% confidence interval] by comparison to the reference TTIGC haplotype were adjusted for cohorts, age and gender, separately in subjects below (diamonds) and above (squares) the population-specific median of BMI. The global test of association was neither significant in the group of individuals below (χ² = 3.767 with 6 df, p = 0.708) nor above (χ² = 10.28 with 6 df, p = 0.113) the median of BMI. Polymorphisms are ordered according to their position on the genomic sequence.

Figure 8

Association between IL18RAP haplotypes and CVD risk in the whole MORGAM cohorts according to BMI. Haplotypic ORs [95% confidence interval] by comparison to the reference TAGTTA haplotype were adjusted for cohorts, age and gender, separately for subjects below (diamonds) and above (squares) the population-specific median of BMI. The global test of association was neither significant in the group of individuals below (χ² = 5.379 with 6 df, p = 0.496) nor above (χ² = 11.18 with 6 df, p = 0.083) the median of BMI. Polymorphisms are ordered according to their position on the genomic sequence.