title: A gene-centric study of common carotid artery remodelling.
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, R(2) = 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), I(2) = 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.
authors.affiliation: Centre for Cardiovascular Genetics, UCL, UK. seamus.harrison@ucl.ac.uk
authors.forename: Seamus C
authors.initials: SC
authors.lastname: Harrison
authors.forename: Delilah
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authors.forename: Kristiina
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authors.lastname: Smit
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authors.lastname: Franco-Cereceda
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authors.lastname: Giral
authors.forename: Elmo
authors.initials: E
authors.lastname: Mannarino
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authors.lastname: Silveira
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Gert J
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authors.lastname: de Borst
authors.forename: Yolanda
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authors.lastname: van der Graaf
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authors.forename: Annette F
authors.initials: AF
authors.lastname: Baas
authors.forename: Jan D
authors.initials: JD
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authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
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authors.lastname: Fowkes
authors.forename: Ionna
authors.initials: I
authors.lastname: Tzoulaki
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Price
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Per
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mesh_terms: D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics* / Q000473:pathology; D017536:Carotid Artery, Common / Q000473:pathology*; D059168:Carotid Intima-Media Thickness / Q000639:trends; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide