A gene-centric study of common carotid artery remodelling

Seamus C. Harrison, Delilah Zabaneh, Folkert W. Asselbergs, Fotios Drenos, Gregory T. Jones, Sonia Shah, Karl Gertow, Bengt Sennblad, Rona J. Strawbridge, Bruna Gigante, Suzanne Holewijn, Jacqueline De Graaf, Sita Vermeulen, Lasse Folkersen, Andre M. van Rij, Damiano Baldassarre, Fabrizio Veglia, Philippa J. Talmud, John E. Deanfield, Obi AguMika Kivimaki, Meena Kumari, Matthew J. Bown, Kristiina Nyyssönen, Rainer Rauramaa, Andries J. Smit, Anders Franco-Cereceda, Philippe Giral, Elmo Mannarino, Angela Silveira, Ann Christine Syvänen, Gert J. de Borst, Yolanda van der Graaf, Ulf de Faire, Annette F. Baas, Jan D. Blankensteijn, Nicholas J. Wareham, Gerry Fowkes, Ionna Tzoulaki, Jacqueline F. Price, Elena Tremoli, Aroon D. Hingorani, Per Eriksson, Anders Hamsten, Steve E. Humphries

Research output: Contribution to journalArticle

Abstract

Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 × 10-8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 × 10-3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

Original languageEnglish
Pages (from-to)440-446
Number of pages7
JournalAtherosclerosis
Volume226
Issue number2
DOIs
Publication statusPublished - Feb 2013

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Keywords

  • Abdominal aortic aneurysm
  • Carotid artery
  • Genome-wide association studies
  • Vascular remodelling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Harrison, S. C., Zabaneh, D., Asselbergs, F. W., Drenos, F., Jones, G. T., Shah, S., Gertow, K., Sennblad, B., Strawbridge, R. J., Gigante, B., Holewijn, S., De Graaf, J., Vermeulen, S., Folkersen, L., van Rij, A. M., Baldassarre, D., Veglia, F., Talmud, P. J., Deanfield, J. E., ... Humphries, S. E. (2013). A gene-centric study of common carotid artery remodelling. Atherosclerosis, 226(2), 440-446. https://doi.org/10.1016/j.atherosclerosis.2012.11.002