Assessment of the association between genetic polymorphisms in transforming growth factor beta, and its binding protein (LTBP), and the presence, and expansion, of Abdominal Aortic Aneurysm

Abstract

Objectives: Abdominal Aortic Aneurysm (AAA) has a strong genetic predisposition. Transforming growth factor beta 1 (TGF-beta1) is a causal factor in ascending aortic dilatation; however, a role in AAA pathology is unclear. The aim of the study was to determine whether genes coding TGF-beta and its binding protein are associated with the presence and expansion of AAA.

Methods: Four geographically distinct case control studies, totaling 1890 AAA cases and 3785 controls, were genotyped and compared to the presence, size and growth rate of AAA. 26 single nucleotide polymorphisms (SNPs) in 5 genes were genotyped in the UK cohort and the result was replicated in 3 independent cohorts.

Results: No associations between genotypes or haplotypes and the presence of AAA disease were confirmed. Five SNPs in Latent TGF-beta Binding Protein (LTBP4) and an allelic variant of TGFB3 were associated with a significant decrease in AAA growth (p< or =0.02), in the UK cohort. Altered growth was demonstrated in carriers of two common haplotypes of LTBP4 (+0.38 mm/year, p=0.003; -0.41 mm/year, p=0.02, per haplotype copy) and a single haplotype of TGFB3 (-0.53 mm/year, p=0.05). This association with AAA growth could not be demonstrated in two other independent cohorts. Meta-analysis of AAA size and growth rates in larger AAA (> or =45 mm), in all four cohorts, demonstrated a significant association with the LTBP4 21011A>T genotype (a 2% decrease in AAA diameter, or a 0.53 mm/year reduction in AAA growth rate, per T allele [p=0.03, p=0.01]).

Conclusion: This study suggests that the LTBP4 gene may contribute to AAA progression.