Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation

Abstract

Summary:We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patient's genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10 ؊1064 and IFN-␥ genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12. and poly-A polymorphisms are in linkage disequilibrium with each other. It is proposed that these polymorphisms exert their effects through enhanced transcription of the VDR gene or through altered mRNA stability. 5,6 The role of vitamin D3 and of the VDR in bone metabolism and turnover is well established. Homozygosity for the closely linked bb and aa genotypes of the BsmI and ApaI RFLPs in intron 8 is associated with increased femoral and vertebral bone density. 3,4,7 Reduced bone loss associated with liver transplantation is less frequent in transplant patients who possess the BsmI and ApaI aa and bb genotypes for VDR. 8 Polymorphism at the ATG initiation codon (FokI site) has been associated with genetic determination of final height in Japanese subjects, with heterozygotes at this locus achieving a greater final height than homozygotes for either allele, 1 and with heritable variation in bone mineral density. 9 Polymorphism at both the FokI and TaqI sites has been associated with variation in intervertebral disc degeneration in males. 10

Variations in 1α,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 serum levels during allogeneic bone marrow transplantation

“…Accordingly, it has been shown that vitamin D analogs prevent acute GvHD in rat BMT and that the VDR gene polymorphism associates with GvHD and survival. 4,5 Up to now, no data are available on the endogenous serum levels of vitamin D metabolites during the course of BMT. In this study we measured 25-hydroxyvitamin D 3 (25(OH)D 3 ) and 1,25(OH) 2 D 3 in consecutive serum samples of 48 patients before and after allogeneic BMT.…”

Effect of vitamin D treatment in chronic GVHD

“…6,7 Previous reports describe the efficacy of a vit D analog MC1288 in preventing acute GVHD in a rat BM transplant model, 8 as well as the relationship between vit D receptor gene polymorphism, and acute and cGVHD. 9 The effects of vit D are mediated by the nuclear vit-D receptor. It is constitutively expressed in monocytes, and in both B-and T-activated lymphocytes.…”

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“…24 A study in 2003 showed that IL10-592A/A compared with C/C genotype was associated with acute GVHD. 25 In 2002, Middleton and associates 26 examined the association between vitamin D receptor polymorphisms and GVHD. They found a significant association between GVHD and vitamin D receptor polymorphism.…”