1. A gene-centric study of common carotid artery remodelling
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Seamus C. Harrison, Ann-Christine Syvänen, Aroon D. Hingorani, Obi Agu, Jan D. Blankensteijn, Anders Hamsten, Rona J. Strawbridge, Gert J. de Borst, Ulf de Faire, Lasse Folkersen, Gerry Fowkes, Mika Kivimäki, Karl Gertow, Elena Tremoli, Ionna Tzoulaki, Kristiina Nyyssönen, John E. Deanfield, Sonia Shah, Delilah Zabaneh, Fabrizio Veglia, Folkert W. Asselbergs, Andre M. van Rij, Bengt Sennblad, Philippa J. Talmud, Steve E. Humphries, Sita H. Vermeulen, Matthew J. Bown, Rainer Rauramaa, Suzanne Holewijn, Anders Franco-Cereceda, Gregory T. Jones, Jacqueline F. Price, Andries J. Smit, Per-Olof Eriksson, Annette F. Baas, Elmo Mannarino, Damiano Baldassarre, Nicholas J. Wareham, Philippe Giral, Meena Kumari, Yolanda van der Graaf, Bruna Gigante, Fotios Drenos, Jacqueline de Graaf, Angela Silveira, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Surgery, and ICaR - Ischemia and repair
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Male ,Vascular remodelling ,Pathology ,Genome-wide association study ,BLOOD-PRESSURE ,030204 cardiovascular system & hematology ,Carotid Intima-Media Thickness ,INTIMA-MEDIA THICKNESS ,Genome-wide association studies ,0302 clinical medicine ,Medicine ,Common carotid artery ,RISK ,0303 health sciences ,Middle Aged ,Phenotype ,Chromosomes, Human, Pair 1 ,CARDIOVASCULAR-DISEASE ,2ND MANIFESTATIONS ,Female ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Carotid Artery, Common ,Polymorphism, Single Nucleotide ,Article ,Vascular remodelling in the embryo ,03 medical and health sciences ,medicine.artery ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Gene ,Genetic Association Studies ,Health aging / healthy living Cardiovascular diseases [IGMD 5] ,METAANALYSIS ,030304 developmental biology ,Aged ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,ABDOMINAL AORTIC-ANEURYSM ,business.industry ,DIAMETER ,Carotid artery.common ,Blood pressure ,Intima-media thickness ,ATHEROSCLEROSIS ,Abdominal aortic aneurysm ,business ,Expansive ,Carotid artery ,Aortic Aneurysm, Abdominal - 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., Highlights ► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.
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