title: Caveolin-1 single nucleotide polymorphism in antineutrophil cytoplasmic antibody associated vasculitis.
abstract: OBJECTIVE
  Immunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV.
  
  
  METHODS
  CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts.
  
  
  RESULTS
  The primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident.
  
  
  CONCLUSIONS
  The presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.
authors.affiliation: Centre for Translational Inflammation Research, University of Birmingham, Birmingham, United Kingdom. sourabh.chand@nhs.net
authors.forename: Sourabh
authors.initials: S
authors.lastname: Chand
authors.forename: Julia U
authors.initials: JU
authors.lastname: Holle
authors.forename: Marc
authors.initials: M
authors.lastname: Hilhorst
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Simmonds
authors.forename: Stuart
authors.initials: S
authors.lastname: Smith
authors.forename: Lavanya
authors.initials: L
authors.lastname: Kamesh
authors.forename: Peter
authors.initials: P
authors.lastname: Hewins
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Cohen Tervaert
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieczorek
authors.forename: Lorraine
authors.initials: L
authors.lastname: Harper
authors.forename: Richard
authors.initials: R
authors.lastname: Borrows
mesh_terms: D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D051242:Caveolin 1 / Q000235:genetics*; D015331:Cohort Studies; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D006113:United Kingdom
chemical_list: D051242:Caveolin 1
references.citation: J Cell Mol Med. 2008 Jun;12(3):796-809
references.pmid: 18315571
references.citation: Shock. 2011 Jan;35(1):92-9
references.pmid: 20601931
references.citation: Eur J Immunol. 2012 Jun;42(6):1500-11
references.pmid: 22678904
references.citation: PLoS One. 2010 Jun 08;5(6):e11004
references.pmid: 20543983
references.citation: Annu Rev Pathol. 2012;7:423-67
references.pmid: 22077552
references.citation: Ann Rheum Dis. 2011 Mar;70(3):488-94
references.pmid: 21109517
references.citation: JAMA. 2010 Apr 7;303(13):1282-7
references.pmid: 20371787
references.citation: Pharmacol Rev. 2002 Sep;54(3):431-67
references.pmid: 12223531
references.citation: N Engl J Med. 2012 Jul 19;367(3):214-23
references.pmid: 22808956
references.citation: Cardiovasc Res. 2005 Oct 1;68(1):128-35
references.pmid: 15950204
references.citation: Am J Hypertens. 2012 Jan;25(1):103-8
references.pmid: 21976276
references.citation: Curr Opin Rheumatol. 2008 Nov;20(6):713-9
references.pmid: 18949888
references.citation: Cardiovasc Res. 2006 Apr 1;70(1):42-9
references.pmid: 16412403
references.citation: J Immunol. 2010 Jan 1;184(1):296-302
references.pmid: 19949109
references.citation: J Am Soc Nephrol. 2007 Jul;18(7):2180-8
references.pmid: 17582159
references.citation: Clin J Am Soc Nephrol. 2013 Feb;8(2):219-24
references.pmid: 23160261