Association of the TGF-β receptor genes with abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor b (TGF-b) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-b pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case-control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a Po0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (Po0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11-1.56 P¼0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12-1.54 P¼0.001 and rs4522809 OR 1.28 95% CI 1.12-1.46 P¼0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options.

Genetic and Epigenetic Regulation of Aortic Aneurysms

“…Much of this focus has been on identifying genes associated with AAA as the heritability of thoracic aneurysms is more commonly recognized [65], although mutational analysis of nonsyndromic thoracic aneurysms has gained interest. Recently, genome-wide association studies (GWAS) have identified several candidate SNPs related to nonsyndromic thoracic aneurysms and AAA [10, 66–68]. Table 1 summarizes genomic and epigenomic relationships with thoracic and abdominal aortic aneurysms.…”

“…Interestingly, AngII increases the expression and activation of all TGF- β isoforms and TGFBR1 and TGFBR2 within both the thoracic and abdominal murine aorta [91–93]. Analysis of the TGFB1 and TGFBR1 genes failed to reveal an association with human AAA [14, 81], but two SNPs in TGFBR2 (rs1036095 and rs4522809) were associated with AAA [10]. Additionally, mutations in the SMAD3 gene have been linked with aneurysm-osteoarthritis syndrome, which further demonstrates the critical role of noncanonical TGF- β in aortic aneurysm formation [22].…”

Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants

“…These observations also have led several groups to indentify associations between polymorphisms in TGF-β pathway and aneurysm. An increased number of studies demonstrated associations of SNPs in TGF-β pathway and abdominal aorta aneurysms [35,36]. In 2013, Wang and coworkers performed, for the first time, mutational analysis on FBN1, TGFBR1 and TGFBR2 genes (the three most common genes causing familial TAA) in 29 TAA Chinese patients (7 affected families and 22 sporadic patients), and found 21 mutations.…”

The pathophysiologic basis of abdominal aortic aneurysm progression: a critical appraisal

“…There is evidence for dysregulation of these factors in AAA disease [118][119][120][121][122]. Yet, available data are currently far from complete and seemingly contradictory [123,124], the latter possibly reflecting different stages of the disease process (i.e., disease initiation vs progression), and the complex regulation of the signaling cascades.…”