Association between Fibrilin1 polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β-1 concentration in human plasma

Abstract

Transforming growth factor β1 (TGF-β1) is associated with different diseases, including aortic aneurysm, as it plays important role in cell proliferation, differentiation and various biological processes. It is known that fibrilin-1 regulates TGF-β1 bioavailability [1]. Mutations in the fibrilin-1 encoding gene FBN1 cause Marfan Syndrome (MFS) and increase in TGF-β signaling significantly contributes to the pathology. FBN1 single nucleotide polymorphisms (SNPs) rs2118181 and rs1059177 are associated with dilatative pathology of aortic aneurysms (DPAA) but do not cause MFS. There is a significant association between TGF-β1 concentration and DPAA (OR 1.084, CI 1.027-1.144, p=0.004). TGF-β1 and FBN1 SNPs rs2118181 and rs1059177 are potential biomarkers for early diagnosis of DPAA. The relationship between TGF-β1 levels in human blood plasma and FBN1 rs2118181 and rs1059177 were investigated in 269 patients. A quantitative dependence of SNP genotype and TGF-β1 concentration was found. Presence of a single rs2118181 minor allele (G) increased the amount of TGF-β1 by roughly 1 ng/ml. But for additive effect on TGF-β1 levels two copies of FBN1 rs1059177 minor allele (G) were required. Higher TGF-β1 concentrations were found in men compared to women (p=0.001). However, TGF-β1 level showed a tendency to increase with age in women (R=0.338, p<0.001) but was steady in men (R=0.105, p=0.288) throughout lifetime. A strong correlation between TGF-β1 levels and FBN1 SNPs suggests that a single nucleotide substitution in FBN1 sequence might reduce bioavailability or binding properties of fibrilin-1 and have an effect on TGF-β1 activation and cytokine concentration in blood plasma. This research not only determines relationship between TGF-β1 and FBN1 SNPs rs2118181 and rs1059177, but also provides evidence that their combination might be used as molecular biomarkers to identify patients at risk for sporadic ascending aortic aneurysm and aortic dissection.