The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm.

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30-7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.

Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy.

Bicuspid aortic valve (BAV) associated with aortopathy is the most common congenital heart disease in the general population. Far from being a simple harmless valve malformation, it can be a complex and heterogeneous disease and a source of chronic and acute pathology (early valvular disease, aneurysm, dissection). In the previous years, intense research has been carried out to find out and understand its mechanisms, but the pathophysiology of the disease is still not fully understood and many questions remain open. Recent studies have discovered several genetic mutations involved in the development of valvular and aortic malformations, but still cannot explain more than 5-10% of cases. Other studies have also focused on molecular alterations and cellular processes (TGF-ß pathway, microRNAs, degradation of the extracellular matrix, metalloproteinases, etc.), being a field in constant search and development, looking for a therapeutic target to prevent the development of the disease. Increased knowledge about this multifaceted disorder, derived from both basic and clinical research, may influence the diagnosis, follow-up, prognosis, and therapies of affected patients in the near future. This review focuses on the latest and outstanding developments on the molecular and genetic investigations of the bicuspid aortopathy.

IL6 gene polymorphism association with calcific aortic valve stenosis and influence on serum levels of interleukin-6.

Aortic valve stenosis is the most frequent valve disease in developed countries and its prevalence will increase with population aging. There is still no pharmaceutical treatment nor biomarker to determine the susceptibility to develop aortic stenosis. Therefore, we analyzed the association of polymorphisms in risk loci with calcific aortic stenosis. Patients with aortic valve disease were genotyped for PALMD rs6702619, LPA rs10455872, and IL6 rs1800795 polymorphisms and circulating levels of interleukin-6 (IL-6) were measured. Calcium content of leaflets obtained in valve replacement surgeries was determined by micro-computed tomography. In the genotyping of 578 individuals, we found significant association between PALMD and IL6 polymorphisms and aortic stenosis in patients with tricuspid aortic valve, independently of other potentially confounding variables such as age and dyslipidemia. There was no association of these polymorphisms with valve calcium content, but this value correlated with the mean aortic pressure gradient (r = 0.44; P < 0.001). The CC genotype of IL6 polymorphism was associated with higher levels of serum IL-6 compared to other genotypes (23.5 vs. 10.5 pg/ml, respectively; P = 0.029). Therefore, patients carrying the CC genotype of IL6 rs1800795 polymorphism present higher levels of circulating IL-6 and this could contribute to the severity of the aortic valve stenosis. Our results agree with the identification of IL6 as a locus risk for stenosis and also with the intervention of this cytokine in aortic valve calcification. A more exhaustive follow-up of those patients carrying risk genotypes is therefore recommended.