title: Comprehensive investigation of the caveolin 2 gene: resequencing and association for kidney transplant outcomes.
abstract: Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study.
authors.affiliation: Nephrology Research Group, Queen's University, Belfast, Northern Ireland. jamccaughan@doctors.org.uk
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McCaughan
authors.forename: Seamus
authors.initials: S
authors.lastname: Duffy
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hagan
authors.forename: Aisling E
authors.initials: AE
authors.lastname: Courtney
authors.forename: Richard
authors.initials: R
authors.lastname: Borrows
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Conlon
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
mesh_terms: D000328:Adult; D051243:Caveolin 2 / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D006085:Graft Survival / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007494:Ireland; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: C495544:CAV2 protein, human; D051243:Caveolin 2