Abstract
BackgroundArterial stiffness has emerged as an important and independent predictor of cardiovascular disease outcome in many populations. A recent GWAS meta‐analysis, the AortaGen Consortium, led by Framingham investigators identified a number of loci on chromosome 14 which associated with aortic pulse wave velocity (aPWV), the current gold standard measure of arterial stiffness. The top signals from this meta‐ analysis lie within non‐coding regions; BCL11B is the closest known gene to this locus. This is a zinc finger protein encoding for CTIP2, a transcriptional repressor involved in regulating vein identity.We hypothesized that one or more of these genetic variants are functional, exerting an effect on BCL11B mRNA levels in human aorta and are clinically relevant, exerting genotype‐specific effects on arterial stiffness. We therefore investigated the influence of 5 polymorphisms from this GWAS (rs1381289C>T, rs6485690G>A, rs10782490C>T, rs1461587G>T and rs17773233G>T) on BCL11B mRNA levels and aortic stiffness measured ex‐vivo as Young's Elastic Modulus (EM) in over 200 aortic tissue samples from cadaveric donors.ObjectiveReplicate findings from the AortaGen Consortium in the source tissue (human aortic samples) and identify polymorphisms that regulate BCL11B gene expression levels and EM.MethodsAortic samples were collected from donors through transplant coordinators at Addenbrooke's Hospital, Cambridge. Demographic data and anthropometric data were recorded. Aortic ring wall thickness and radii were measured and EM was obtained using the tensile compression test machine Instron 5542. DNA and RNA were extracted from the samples following standard procedures. SNP genotyping and BCL11B gene expression levels were determined using ABI assays. All samples and donor data were handled in accordance with the policies and procedures of the Human Tissue Act and the study was approved by the Local and Regional Ethics Committees.ResultsMean age of the study sample was 57 ± 15 years. EM correlated significantly with age (r= 0.47, P<0.001). BCL11B gene expression levels were higher in subjects carrying rs1381289 T and rs10782490 C alleles (P <0.05). rs1461587G>T and rs17773233G>T polymorphisms showed genotype specific higher EM values (P<0.05). Multiple regression adjusted for confounders showed rs1461587G>T and rs17773233G>T associated with increased EM (beta=−0.15, P<0.05) and (beta=0.17, P<0.05) respectively.ConclusionsWe have demonstrated that BCL11B gene expression levels are driven by distal polymorphisms within the BCL11B gene desert on chromosome 14. These gene variants may be important in mediating structural and functional changes to the arterial wall that lead to the manifestation of arterial stiffness. Further functional characterisation will aid in confirming the role of this region in the stiffening of arteries.Support or Funding InformationBritish Heart Foundation and Addenbrookes Charitable Trust.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have