Association of High Expression TGFb Genotypes with Severe GVHD, Veno-occlusive Disease (VOD) and Cytokine Release Syndrome (CR) in Bone Marrow Transplantation(BMT).
MS Leffell, GB Vogelsang, DP Lucas, NL Delaney and AA Zachary. Johns Hopkins University School of Medicine, Baltimore, MD.

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To investigate if alleles of cytokine genes affecting expression levels could be associated with graft versus host disease (GVHD) or other complications of BMT, we determined TNF?, IL-6, IL-10, IFN? and TGF? alleles in 84 donor-recipient allogeneic BMT pairs. The recipients included 25 who experienced severe GVHD(Grade II-IV); 19 with VOD and 16 with CR. The control group included 24 patients with no or mild GVHD (Grade<II) and no other complications. All grafts were from HLA-identical siblings except for five cases in the severe GVHD group who received grafts from phenotypically HLA matched, unrelated donors. Cytokine alleles were determined from QIAamp7 extracted DNA by PCR-SSP. The distribution of individual cytokine alleles among the different patient and donor groups, the combined effect of individual alleles in donor:recipient pairs, and different paired cytokine phenotypes were evaluated. No significant differences were observed in the distribution of alleles for IL-6, IL-10 and IFN? among the patient and donor groups. The frequency of the GG low expression genotype of TNF? was increased among patients with VOD and approached significance (P=0.055). Genotypes of high expression of TGF? ( T/T G/G;T/C G/G) were significantly increased among recipients with CR(P=0.024), GVHD (P=0.016) and VOD (P<0.001). There was a highly significant increase in the GG genotype at codon 25 for TGF? among all patients with severe complications compared to the control recipients (P<0.001). Considering combined genotypes of donor: recipient pairs, in 76.5% of control pairs, both members had low expression TGF? phenotypes compared to 14.3%of pairs in the severe GVHD group (P<0.001).