The TGFβ system and TIMP1 and 3 genotypes in Turner syndrome—Relation with aortic congenital malformations

Abstract

ObjectiveCardiovascular complications and congenital malformations are known traits in Turner syndrome (TS), which increases mortality. Women with TS have varying phenotype and cardiovascular risks. A biomarker assessing the risk for cardiovascular complications could potentially reduce mortality in high‐risk TS and reduce screening in TS participants with low cardiovascular risk.Design, Patients, Participants and MeasurementsAs part of a study initiated in 2002, 87 TS participants and 64 controls were invited to magnetic resonance imaging of the aorta, anthropometry, and biochemical markers. TS participants were re‐examined thrice lastly in 2016. The focus of this paper is the additional measurements of transforming growth factor beta (TGFβ), matrix metalloproteinase (MMP's), tissue inhibitor of matrix metalloproteinase (TIMP), peripheral blood DNA and their associations with TS and the cardiovascular risk and congenital heart disease.ResultsTS participants had lower TGFβ1 and TGFβ2 values compared to controls. snp11547635 heterozygosity was not associated with any biomarkers but was associated with increased risk of aortic regurgitation. TIMP4 and TGFβ1 were correlated with the aortic diameter at several measuring positions. During follow‐up, the antihypertensive treatment decreased the descending aortic diameter and increased TGFβ1 and TGFβ2 levels in TS.ConclusionTGFβ and TIMP's are altered in TS and may play a role in the development of coarctation and dilated aorta. snp11547635 heterozygosity was not found to impact biochemical markers. Further studies should investigate these biomarkers to further unravel the pathogenesis of the increased cardiovascular risk in TS participants.

Analysis of genetic variability in Turner syndrome linked to long-term clinical features

“…It is hypothesized that loss of TIMP1 (on the X chromosome) coupled with variations in TIMP3 can predispose to CCA in women with TS, in an autosomal “two-hit” hypothesis ( 2 , 35 , 36 ). Very recently, the rs11547635 variant (22:32857305:C-T) in TIMP3 has also been associated with aortic regurgitation in a longer term follow up study of Turner women ( 52 ). Notably, we were able to replicate the enrichment of this 22:32857305:C-T variant with CCA in our cohort ( Table 3 ).…”

Imbalance of fetal growth factor levels in congenital heart disease pathology: a systematic review to investigate therapeutic potential

“…Downregulated growth factor expression or dysregulation is the main cause of CHD, but it may be treated from another perspective. The set of pseudohormones that stimulate the growth of the heart and blood vessels during the fetal period are associated with gene expression disorders or loss of function (12,13). Increased expression of VEGF in the fetal stage is associated with the occurrence of CHD if its expression decreases after birth, and this in turn is considered to have therapeutic potential.…”