TY - JOUR
T1 - Caveolin-1 Single Nucleotide Polymorphism in Antineutrophil Cytoplasmic Antibody Associated Vasculitis
AU - Chand, Sourabh
AU - Holle, Julia U.
AU - Hilhorst, Marc
AU - Simmonds, Matthew J.
AU - Smith, Stuart
AU - Kamesh, Lavanya
AU - Hewins, Peter
AU - McKnight, Amy Jayne
AU - Maxwell, Alexander P.
AU - Tervaert, Jan Willem Cohen
AU - Wieczorek, Stefan
AU - Harper, Lorraine
AU - Borrows, Richard
PY - 2013/7/19
Y1 - 2013/7/19
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0069022
DO - 10.1371/journal.pone.0069022
M3 - Article
C2 - 23894397
SN - 1932-6203
VL - 8
JO - PLOS ONE
JF - PLOS ONE
IS - 7
ER -