title: Integrated multiomics approach identifies calcium and integrin-binding protein-2 as a novel gene for pulse wave velocity.
abstract: BACKGROUND
  Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV.
  
  
  RESULTS
  We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [β = -0.359, standard error (SE) = 0.07, P = 4.8 × 10]. The same variant was also associated with increased CIB2 expression in leucocytes (β = 0.034, SE = 0.008, P = 4.95 × 10) and skin (β = 0.072, SE = 0.01, P = 2.35 × 10) and with hypomethylation of the gene promoter (β = -0.899, SE = 0.098, P = 3.63 × 10).
  
  
  CONCLUSIONS
  Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms.
authors.affiliation: aDepartment of Twin Research and Genetic Epidemiology, King's College London bNIHR Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust cDepartment of Clinical Pharmacology, King's College London dThe Institute of Cancer Research, London, UK eCardiovascular Engineering, Inc, Norwood, Massachusetts, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Marina
authors.initials: M
authors.lastname: Cecelja
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: Kerrin
authors.initials: K
authors.lastname: Small
authors.forename: Jordana
authors.initials: J
authors.lastname: Bell
authors.forename: Gary F
authors.initials: GF
authors.lastname: Mitchell
authors.forename: Phillip
authors.initials: P
authors.lastname: Chowienczyk
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D002339:Carotid Arteries / Q000502:physiology; D002884:Chromosomes, Human, Pair 15; D019175:DNA Methylation / Q000235:genetics; D030541:Databases, Genetic; D057890:Epigenomics; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D063177:Pulse Wave Analysis; D012867:Skin / Q000378:metabolism*; D059467:Transcriptome; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: C577150:CIB2 protein, human; D002135:Calcium-Binding Proteins; D002118:Calcium