Exploration of the Genetic Basis of GVHD by Genetic Association Studies

Ogawa, Seishi; Matsubara, Aiko; Onizuka, Makoto; Kashiwase, Koichi; Sanada, Masashi; Kato, Motohiro; Nannya, Yasuhito; Akatsuka, Yoshiki; Satake, Masahiro; Takita, Junko; Saji, Hiroo; Maruya, Etsuko; Inoko, Hidetoshi; Morishima, Yasuo; Kodera, Yoshihisa; Sasazuki, Takehiko

doi:10.1016/j.bbmt.2008.11.020

Cited by 20 publications

(16 citation statements)

References 17 publications

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“…Possible false-positive findings arising from multiple testing involving the 306 samples were evaluated by maintaining the false discovery rate under 0.01 as previously described, 16 where the microarray data of 1000 JMDP donor specimens obtained from an ongoing whole genome association study (unpublished data) were used to calculate an empiric null distribution. 17,18 Determination of the missing HLA alleles in 6pLOH(؉) clones in patients with AA…”

Section: Analysis Of Genomic Copy Numbers and Detection Of 6plohmentioning

confidence: 99%

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

Katagiri

Sato‐Otsubo

Kashiwase

et al. 2011

Blood

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157

177

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Section: Analysis Of Genomic Copy Numbers and Detection Of 6plohmentioning

confidence: 99%

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

Katagiri

Sato‐Otsubo

Kashiwase

et al. 2011

Blood

Self Cite

157

177

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“…It is thought that a large proportion of risk for adverse outcomes after hematopoietic stem cell transplantation (HSCT) is genetic, attributed to HLA matching, 1 killer-immunoglobulin-like receptor matching, 2,3 minor histocompatibility antigens, 4,5 and non-HLA gene polymorphisms. 6 Whereas the degree of HLA mismatching exerts the strongest genetic effect on risks, such as acute and chronic GVHD, relapse, and survival, non-HLA polymorphisms in immune response genes, such as cytokines, at least modify these risks, as shown in studies that have shown light on the pathobiology of HSCT, 7,8 and the relation of cytokine gene polymorphisms, 6,9,10 with gene expression and biologic effects.…”

Section: Introductionmentioning

confidence: 99%

“…Most of these studies used a candidate gene approach, and only one study was a genome-wide association study. 5 To minimize genetic confounding, most of these studies used either fully or largely HLA-matched related or unrelated HSCT cohorts. Limited availability of study subjects in the past made consideration of demographic or clinical risk factors in study cohort selection difficult, despite the existence of these risks being well established in the literature (eg, patient and donor age, 16,17 female donor to male recipient, 18 diagnosis and staging, prior chemotherapy, conditioning regimen, 19 concurrent infections).…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study

Harkensee

Oka

Onizuka

et al. 2012

Blood

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“…87 A large genome-wide association study in Japanese patients identified a SNP in the HLA-DP region at which donor/recipient mismatch was significantly associated with GVHD. 88 In addition, 3 large retrospective analyses of HLA-DP matching in unrelated donor HCT have found significant associations between matching status and the incidence of relapse after transplantation. 77,89,90 A number of studies have suggested that not all HLA-DP mismatches are equivalent and have led to a model of "permissive" and "nonpermissive" mismatches, 84,[91][92][93][94] but this model conflicts with results of several recent laboratory studies of HLA-DPspecific T-cell alloreactivity.…”

mentioning

confidence: 99%

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

Warren

Zhang

et al. 2012

Blood

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The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome. The enormous variation that characterizes the human genome suggests that the total number of minor H loci is probably large and ensures that all donor/ recipient pairs, despite selection for identity at the MHC, will be mismatched for many minor H antigens. In addition to mismatch at minor H loci, unrelated donor/ recipient pairs exhibit genetic disparity at numerous loci within the MHC, particularly HLA-DP, despite selection for identity at HLA-A, -B, -C, and -DRB1. Disparity at HLA-DP exists in 80% of unrelated pairs and clearly influences the outcome of unrelated hematopoietic cell transplantation; the magnitude of this effect probably exceeds that associated with disparity at any locus outside the MHC. (Blood. 2012;120(14):2796-2806) IntroductionGenetic nonidentity between donor and recipient is the key to the therapeutic efficacy of allogeneic hematopoietic cell transplantation (HCT) for malignant disease, but it is also the root of GVHD, its primary limitation. Pioneering studies in the late 1960s and early 1970s led to the critical discovery that donor/recipient genetic nonidentity at the MHC on chromosome 6p is the single most important risk factor for the development of severe GVHD. 1 The subsequent implementation of donor selection procedures according to donor/recipient MHC matching established with serologic assays and mixed lymphocyte culture revolutionized the nascent field of allogeneic marrow transplantation and enabled rapid growth during the subsequent decade in the annual number of transplantations performed, as well as considerable improvement in the likelihood of a successful transplantation outcome. Nonetheless, clinically significant GVHD still developed in a sizeable fraction of recipients of bone marrow grafts from sibling donors with whom they were genotypically identical throughout the MHC region on both copies of chromosome 6p. This observation suggested that genetic loci outside the MHC, encoding putative histocompatibility determinants that were collectively referred to as minor histocompatibility (H) antigens, could also influence a recipient's likelihood of developing GVHD or benefitting from GVL activity. 1,2 The intervening years have witnessed steady progress in elucidating the nature of minor H antigens and the genes that encode them and have seen the identification and characterization of other complex genetic loci that also influence histocompatibility in the allogeneic HCT setting. Here, we review the manner in which g...

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Exploration of the Genetic Basis of GVHD by Genetic Association Studies

Cited by 20 publications

References 17 publications

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia

Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

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