Genetic Variations on Chromosome 14 Influence BCL11B Gene Expression Levels and Aortic Stiffness

• DOI: 10.1096/fasebj.30.1_supplement.1260.8
• Publication Date: 2023-11-26T16:51:37Z
• Authors: Raya Al Maskari; Sarah Cleary; Ye Li; Ashraf Khir; Gary Mitchell; Ian Wilkinson; Kevin O'Shaughnessy; Yasmin
• Keywords: Genome-wide Association Study; Candidate gene

Background Arterial 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 loci on chromosome 14 which associated with aortic pulse wave velocity (aPWV), current gold standard measure arterial stiffness. The top signals from this meta‐ analysis lie within non‐coding regions; BCL11B is closest known gene to locus. This zinc finger protein encoding for CTIP2, transcriptional repressor involved regulating vein identity. We hypothesized that one or more these genetic variants are functional, exerting effect mRNA levels human aorta clinically relevant, genotype‐specific effects therefore investigated influence 5 polymorphisms (rs1381289C>T, rs6485690G>A, rs10782490C>T, rs1461587G>T rs17773233G>T) measured ex‐vivo Young's Elastic Modulus (EM) over 200 tissue samples cadaveric donors. Objective Replicate findings source (human samples) identify regulate expression EM. Methods Aortic were collected donors through transplant coordinators at Addenbrooke's Hospital, Cambridge. Demographic data anthropometric recorded. ring wall thickness radii EM was obtained using tensile compression test machine Instron 5542. DNA RNA extracted following procedures. SNP genotyping determined ABI assays. All donor handled accordance policies procedures Human Tissue Act study approved Local Regional Ethics Committees. Results Mean age sample 57 ± 15 years. correlated significantly (r= 0.47, P<0.001). higher subjects carrying rs1381289 T rs10782490 C alleles (P <0.05). rs17773233G>T showed genotype specific values (P<0.05). Multiple regression adjusted confounders increased (beta=−0.15, P<0.05) (beta=0.17, respectively. Conclusions have demonstrated driven distal desert 14. These may be mediating structural functional changes lead manifestation Further characterisation will aid confirming role region stiffening arteries. Support Funding Information British Heart Foundation Addenbrookes Charitable Trust.