Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA‐matched sibling hematopoietic stem cell transplantation

Abstract

We hypothesized that polymorphisms of the vitamin D receptor (VDR) gene might affect clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). Three VDR gene polymorphisms (BsmI G>A, ApaI G>T, and TaqI T>C) were genotyped in 147 patients who underwent HLA-matched sibling allogeneic HSCT. Frequencies of infection, graft-vs.-host disease (GVHD), overall survival (OS), and disease-free survival (DFS) were compared according to genotypes and haplotypes. Infection and acute GVHD had trends to be less frequent in patients with ApaI TT genotype than non-TT genotypes (p = 0.061 and p = 0.059, respectively). For TaqI genotypes, there were no statistical differences in frequency of infection and acute GVHD (p = 0.84 and p = 0.30, respectively), but TC genotype was associated with longer OS and DFS than TT genotype (p = 0.022 and p = 0.038, respectively). In the ApaI-TaqI haplotype analysis, patients with TC haplotype had significantly longer OS and DFS than those without TC haplotype (p = 0.022 and p = 0.038, respectively). In multivariable analysis, TaqI genotype and ApaI-TaqI haplotype of recipients were independent prognostic factors for both OS and DFS. This study suggests that the genotype and haplotype of VDR in recipient might be associated with clinical outcome of sibling HLA-matched HSCT.

The Role of Vitamin D in Hematologic Disease and Stem Cell Transplantation

“…The functional significance of this allelic variation is unknown and no direct link to high or low VDR activity is reported. This study also found that recipients having two copies of the “A” allele for the Apa I polymorphism experienced decreased rates of acute GVHD and infection [37]. Polymorphisms of Apa I have been correlated to VDR activity with homozygosity for the “a” allele associated with higher VDR activity [4].…”

“…They analyzed recipient VDR polymorphisms and retrospectively evaluated the association with patient outcomes including infection, GVHD, overall survival (OS) and disease free survival (DFS) [37]. The most significant findings were a correlation between polymorphisms at the Taq 1 cleavage site where heterozygotes, (those possessing at least one copy of the C allele), had better disease free survival (DFS) and overall survival than TT homozygotes [37]. The functional significance of this allelic variation is unknown and no direct link to high or low VDR activity is reported.…”

“…This would suggest a wide range of therapeutic potential if these relationships can be better understood. Despite the fact that vitamin D through the VDR usually plays an immune modulatory role, it appears that the most vigorous phenotype of the vitamin D receptor, when present in the recipients of HSCT leads to worse GVHD and worse outcomes [4,6,37]. This is suggested to be due to a particular role of stimulating the immediate immune response and cytokine storm that initiates GVHD, which is likely through a paracrine effect with its presence in recipient tissue [4].…”

Identification and Utilization of Donor and Recipient Genetic Variants to Predict Survival After HCT: Are We Ready for Primetime?

“…Candidate gene studies have tested SNP associations with cause-specific (TRM and DRM) and overall survival in redox metabolism genes ( GSTM1 , UGT2B17 ) [ 16 , 17 ] and cytokine and chemokine genes and their receptors ( IL7 receptor-α , IL-10 and TNF-α , IL-1 , IL-1-β , IL-1-α , IL-6 , IL-10 , IL-10R , IL-23 , IL23R , CCL2 , CCR5 , TLR9 ) in both donors and recipients [ 18 – 30 ]. Other studies focused on variants in genes responsible for immune response and recognition including FCGR3A [ 31 ], CTLA4 [ 23 , 24 , 32 – 35 ], LCT [ 36 ], and NOD2/CARD15 [ 37 – 49 ], as well as VDR [ 50 – 54 ] and MTHFR [ 54 , 55 ] and THBD [ 56 ]. Initial results were promising, reviewed in [ 57 ], and yielded some significant associations with overall survival (OS) and TRM after related and unrelated donor HCT.…”

The major histocompatibility complex: a model for understanding graft-versus-host disease

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] The individual contribution from each of these factors and pathways may be challenging to quantify in individual patients; however sophisticated tools and analysis methods are available for assessing the global impact of genetic variation on transplant outcome.…”