title: Common CCR5-del32 frameshift mutation associated with serum levels of inflammatory markers and cardiovascular disease risk in the Bruneck population.
abstract: OBJECTIVE
  Atherosclerosis is a progressive inflammatory disease and can develop in large arteries such as carotid and femoral arteries or medium-sized muscular arteries of the heart. Previous predominantly experimental studies suggested an important role of chemokines in the development of atherosclerosis. The main aim of this study was to examine potential effect of the CCR5-del32 mutation on systemic inflammation, intima-media thickness in carotid and femoral arteries, and on the indices of cardiovascular disease.
  
  
  METHODS
  In the present study, we have examined the association of a common functional 32-bp frameshift deletion mutation in a chemokine receptor (CCR5) in relation to inflammation and atherosclerosis. CCR5 is a G protein-coupled receptor involved in inflammatory response and regulation of leukocytes activation and migration. Genetic screening of this mutation was carried out on a well-known and previously described cohort of Bruneck (n=826) using polymerase chain reaction.
  
  
  RESULTS
  Screening was successful in 810 subjects of whom 7 were homozygous, 102 were heterozygous, and 701 were normal. The mutation was associated with significantly lower levels of C-reactive protein in a dose-dependent manner. Moreover, CCR5-del32 was associated with a significantly lower carotid intima-media thickness in the common carotid artery (del32/del32, 837+/-8 microm; wt/del32, 909+/-21 microm; wt/wt, 958+/-8 microm; P=0.007 after multivariable adjustment). Furthermore, incident cardiovascular disease (1995 to 2005) was markedly reduced in del32 homozygotes and heterozygotes subjects compared with wild-type homozygotes (del32/del32=0%, wt/del32=7.8%, wt/wt=14.8%, P=0.020). Findings equally applied to coronary artery and cerebrovascular disease.
  
  
  CONCLUSIONS
  The chemokine receptor CCR5-del32 frameshift mutation is associated with low levels of C-reactive protein, decreased intima-media thickness, and cardiovascular disease risk. These findings are consistent with the hypothesis that the chemokine receptor CCR5 is involved in the mediation of low-grade systemic inflammation and may play a role in human atherosclerosis and cardiovascular disease.
authors.affiliation: Department of Clinical Developmental Sciences, St George's University of London, London, SW17 ORE, UK. a_r_afzal@yahoo.co.uk
authors.forename: Ali R
authors.initials: AR
authors.lastname: Afzal
authors.forename: Stefan
authors.initials: S
authors.lastname: Kiechl
authors.forename: Yousef P
authors.initials: YP
authors.lastname: Daryani
authors.forename: Arusha
authors.initials: A
authors.lastname: Weerasinghe
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Agnes
authors.initials: A
authors.lastname: Mayr
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weger
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Johann
authors.initials: J
authors.lastname: Willeit
mesh_terms: D000328:Adult; D000368:Aged; D001158:Arteries / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics; D002097:C-Reactive Protein / Q000096:biosynthesis; D002318:Cardiovascular Diseases / Q000097:blood*; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000235:genetics* / Q000502:physiology*; D012306:Risk
chemical_list: D019713:Receptors, CCR5; D002097:C-Reactive Protein