C-reactive protein polymorphism rs3091244 is associated with abdominal aortic aneurysm

BackgroundAbdominal aortic aneurysm (AAA) formation involves an inflammatory process with a strong genetic background. C-reactive protein (CRP) regulates inflammation and is elevated in patients with AAA. The aim of this study was to investigate the association of the triallelic (C, A, and T alleles) rs3091244 functional CRP single nucleotide polymorphism (SNP) with AAA.MethodsThis was a case-control study involving two independent populations: 351 AAA patients (mean aortic diameter, 6.25 ± 1.47 cm) and 391 controls (mean diameter, 2.4 ± 0.2 cm) were recruited from Greece (the main cohort); and 371 patients (mean diameter, 5.4 ± 1.0 cm) and 362 controls (mean diameter, 2.4 ± 0.6 cm) were recruited from the United Kingdom (replication cohort). The frequency of the functional triallelic (C, T, and A alleles) rs3091244 polymorphism was analyzed in univariate and adjusted (for cardiovascular risk factors) analyses, assuming that the rare T and A alleles have similar functional properties (pooled analysis for T and A). Three groups were constructed: group A included those with the rare T and A alleles (genotypes TT, AA, and TA), group B included heterozygotes for the C allele (CT, CA), and group C included C allele homozygotes (CC, reference genotype). Finally, meta-analysis of the two populations was performed together with previously reported results.ResultsGenotype distributions differed significantly between cases and controls in both cohorts (P < .001 and P = .001). Adjusted analysis (for all aneurysm-related risk-factors) showed an estimated odds ratio of 4.88 (95% confidence interval [CI], 2.96-8.04) for SNP group A and 2.38 (95% CI, 1.69-3.36) for SNP group B (P < .001 in both cases) in the initial cohort and 2.07 (95% CI, 1.33-3.21) for SNP group A and 1.70 (95% CI, 1.21-2.39) for SNP group B (P = .001 and .002) in the replication cohort. The SNP group A patients among the main cohort also had higher CRP levels (median, 26; interquartile range, 17-52 mg/L vs median, 4; interquartile range, 4-12 mg/L; P < .001). Aneurysms >5.5 cm were significantly more frequent among the SNP groups A and B compared with C allele homozygotes both in the main and the replication cohorts (P < .001 and P = .001, respectively). Meta-analysis of the two populations with previously reported results showed a positive association between minor-allele and aneurysm presence with an odds ratio of 1.47 (95% CI, 1.01-2.14; I2 = 83.1%; P = .04).ConclusionsThe rare T and A alleles were significantly related with AAA presence in both populations and correlated with higher CRP levels and AAA diameter.

Clinical RelevanceAbdominal aortic aneurysm (AAA) constitutes a significant health problem. Several environmental factors are implicated, but the disease is recognized to have a strong genetic component. Those with a first-degree relative with AAA have up to an 11-fold increased risk of developing the disease themselves. This study identifies a novel genetic marker that was strongly correlated with AAA presence and size. This may help identify those at risk of developing an AAA, especially of a large diameter. Additionally, the fact that this marker was correlated with raised C-reactive protein levels, points toward a strong inflammatory process underlying AAA formation.