Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogenei...Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogeneic transplantation.Moreover,aGVHD remains a cause of mortality after HLA-matched allogeneic transplantation.Protocols for HLA-haploidentical hematopoietic cell transplantation(haploHCT)have been established successfully and widely applied,further highlighting the urgency of performing panoramic screening of non-HLA variations correlated with aGVHD.On the basis of our time-consecutive large haploHCT cohort(with a homogenous discovery set and an extended confirmatory set),we first delineated the genetic landscape of 1366 samples to quantitatively model aGVHD risk by assessing the contributions of HLA and non-HLA genes together with clinical factors.In addition to identifying multiple loss-of-function(LoF)risk variations in non-HLA coding genes,our data-driven study revealed that non-HLA genetic variations,independent of HLA disparity,contributed the most to the occurrence of aGVHD.This unexpected major effect was verified in an independent cohort that received HLA-identical sibling HCT.Subsequent functional experiments further revealed the roles of a representative non-HLA LoF gene and LoF gene pair in regulating the alloreactivity of primary human T cells.Our findings highlight the importance of non-HLA genetic risk in the new era of transplantation and propose a new direction to explore the immunogenetic mechanism of alloreactivity and to optimize donor selection strategies for allogeneic transplantation.展开更多
基金supported by the Major Program of the National Natural Science Foundation of China(No.82293630)the Peking University Medicine Fund for the world’s leading discipline or discipline cluster development(No.71003Y3035)+1 种基金the National Key Research and Development Program of China(Nos.2022YFA0103300,2017YFA0104500,and 2016YFC0901603)the State Key Laboratory of Gene Function and Modulation Research and the Beijing Advanced Innovation Center for Genomics(ICG)at Peking University.
文摘Human leukocyte antigen(HLA)disparity between donors and recipients is a key determinant triggering intense alloreactivity,leading to a lethal complication,namely,acute graft-versus-host disease(aGVHD),after allogeneic transplantation.Moreover,aGVHD remains a cause of mortality after HLA-matched allogeneic transplantation.Protocols for HLA-haploidentical hematopoietic cell transplantation(haploHCT)have been established successfully and widely applied,further highlighting the urgency of performing panoramic screening of non-HLA variations correlated with aGVHD.On the basis of our time-consecutive large haploHCT cohort(with a homogenous discovery set and an extended confirmatory set),we first delineated the genetic landscape of 1366 samples to quantitatively model aGVHD risk by assessing the contributions of HLA and non-HLA genes together with clinical factors.In addition to identifying multiple loss-of-function(LoF)risk variations in non-HLA coding genes,our data-driven study revealed that non-HLA genetic variations,independent of HLA disparity,contributed the most to the occurrence of aGVHD.This unexpected major effect was verified in an independent cohort that received HLA-identical sibling HCT.Subsequent functional experiments further revealed the roles of a representative non-HLA LoF gene and LoF gene pair in regulating the alloreactivity of primary human T cells.Our findings highlight the importance of non-HLA genetic risk in the new era of transplantation and propose a new direction to explore the immunogenetic mechanism of alloreactivity and to optimize donor selection strategies for allogeneic transplantation.
