title: Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia.
abstract: BACKGROUND
  The P2X7 receptor is a ligand-gated cation channel that mediates ATP-induced apoptotic death in haemopoietic and chronic lymphocytic leukaemia (CLL) cells. We aimed to investigate the clinical effect of a single nucleotide polymorphism in the P2X7 receptor gene (1513A-->C) and correlate findings with the immunoglobulin heavy chain variable (V(H)) gene mutation status, a prognostic marker in CLL.
  
  
  METHODS
  We investigated tumour DNA in 170 patients with CLL using PCR-RFLP analysis with HhaI restriction enzyme cleavage to screen for the polymorphism in the P2X7 receptor gene. The VH gene mutation status was assessed in 165 patients by PCR amplification and nucleotide sequencing. We correlated the findings of the P2X7 receptor genotype with the V(H) gene mutation data and overall survival and screened for the P2X7 receptor polymorphism in 200 healthy controls.
  
  
  RESULTS
  Of the 170 patients, 35 (21%) were heterozygous and one (1%) homozygous for the 1513C allele; whereas 134 (79%) had the 1513A/A genotype of the P2X7 receptor gene. Overall survival was significantly longer for patients with CLL heterozygous for the 1513C allele than those with the 1513A/A genotype. Median survival for heterozygous patients was 104 months (range 33-467) and 72 months (1-190) for homozygous patients (p=0.009). Of the 165 patients with CLL in whom we assessed the V(H) gene mutation status, the V(H) genes were mutated in 71 (43%) patients and unmutated in 94; 18 (25%) of the 71 patients with mutated genes had 1513C allele compared with 17 (18%) of 94 who had unmutated genes. In patients with mutated VH genes, those with CLL who were 1513C positive had 53 months' longer median survival than did those with the 1513A/A genotype (151 vs 98 months, p=0.011).
  
  
  CONCLUSIONS
  The P2X7 polymorphism could affect clinical outcome in CLL, especially in patients with mutated V(H) genes. Studies are necessary to elucidate the biological role of the P2X7 polymorphism in CLL in vivo.
authors.affiliation: Department of Oncology, Uppsala University, Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Thunberg
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobin
authors.forename: Anna
authors.initials: A
authors.lastname: Johnson
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Magnus
authors.initials: M
authors.lastname: Hultdin
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.forename: Christer
authors.initials: C
authors.lastname: Sundström
authors.forename: Göran
authors.initials: G
authors.lastname: Roos
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058486:Receptors, Purinergic P2X7
chemical_list: C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7