title: Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft-versus-host disease after sibling allogeneic bone marrow transplantation.
abstract: BACKGROUND
  A single nucleotide polymorphism in the tumor necrosis factor type II receptor (TNFRII) gene, codon 196, results in the substitution of arginine (R allele) for methionine (M allele). The 196R allele is reportedly associated with an increased susceptibility to autoimmune disease, and donor 196R allele carriage correlates with increased severity of acute graft-versus-host disease (GVHD) after matched unrelated bone marrow transplantation (BMT).
  
  
  METHODS
  We investigated the impact of donor and recipient TNFRII genotype on GVHD incidence and severity among 104 adult recipients of myeloablative sibling BMTs.
  
  
  RESULTS
  196R allele frequency was 0.28 among recipients, donors, and controls. There was an increased incidence of acute GVHD among 196R-positive recipients (odds ratio [OR] 3.6, P=0.05). This association was confirmed in multivariate analysis (relative risk 4, P=0.04), correcting for previously established clinical and genetic risk factors. Donor 196R homozygosity was associated with an increased incidence of extensive chronic GVHD (OR 18.5, P=0.02). This association was also confirmed in multivariate analysis (OR 11, P=0.02). To investigate the functional impact of the TNFRII 196 M/R polymorphism, 79 volunteer blood donors were genotyped at this locus, by polymerase chain reaction and single-strand conformational polymorphism analysis, and plasma soluble TNFRII (sTNFRII) levels were measured by ELISA. Mean plasma sTNFRII levels (pg/mL: +/-SEM) were 1224 (+/-26) and 1063 (+/-65) for 196M-postive (196 M homozygous or heterozygous) individuals and 196R homozygotes, respectively (P=0.02).
  
  
  CONCLUSIONS
  Because sTNFRIIs can act as TNF antagonists, the association between recipient and donor TNFRII 196R allele status and acute or extensive chronic GVHD incidence, respectively, may reflect reduced circulating sTNFRII.
authors.affiliation: Department of Haematology, Royal Victoria Infirmary, University of Newcastle, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom. g.l.stark@ncl.ac.uk
authors.forename: Gail L
authors.initials: GL
authors.lastname: Stark
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dickinson
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.forename: Penelope R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Proctor
authors.forename: Peter G
authors.initials: PG
authors.lastname: Middleton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood* / Q000235:genetics*; D016025:Bone Transplantation / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007938:Leukemia / Q000145:classification / Q000601:surgery; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood* / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II; D012016:Reference Values; D035781:Siblings; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II