title: Evaluation of published single nucleotide polymorphisms associated with acute GVHD.
abstract: Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P = .011) and recessive (adjusted P = .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P = .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. jchien@fhcrc.org
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
authors.forename: Xinyi Cindy
authors.initials: XC
authors.lastname: Zhang
authors.forename: Wenhong
authors.initials: W
authors.lastname: Fan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Lue Ping
authors.initials: LP
authors.lastname: Zhao
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Martin
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
authors.forename: Edus H
authors.initials: EH
authors.lastname: Warren
authors.forename: John A
authors.initials: JA
authors.lastname: Hansen
mesh_terms: D000208:Acute Disease; D000328:Adult; D000483:Alleles; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005966:Glucuronidase / Q000235:genetics*; D006086:Graft vs Host Disease / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014184:Transplantation, Homologous; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D016753:Interleukin-10; D007376:Interleukin-2; D015850:Interleukin-6; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000099175:Heparanase; C508609:IL10 protein, human; C508594:IL2 protein, human; C508600:IL6 protein, human; C573423:MTHFR protein, human