Patient HLA Germline Variation and Transplant Survivorship
Menée auprès d'une cohorte de 1 555 patients ayant bénéficié d'une greffe de cellules souches hématopoïétiques non HLA compatibles puis validée sur 3 061 patients complémentaires, cette étude évalue l'association entre la présence de polymorphismes constitutionnels à simple nucléotide au niveau des régions codant pour les antigènes HLA et la survie des patients après la greffe
Purpose : HLA mismatching increases mortality after unrelated donor hematopoietic cell transplantation. The role of the patient’s germline variation on survival is not known.
Patients and Methods : We previously identified 12 single nucleotide polymorphisms within the HLA region as markers of transplantation determinants and tested these in an independent cohort of 1,555 HLA-mismatched unrelated transplants. Linkage disequilibrium mapping across class II identified candidate susceptibility features. The candidate gene was confirmed in an independent cohort of 3,061 patients.
Results : Patient rs429916AA/AC was associated with increased transplantation-related mortality compared with rs429916CC (hazard ratio [HR], 1.39; 95% CI, 1.12 to 1.73; P = .003); rs429916A positivity was a proxy for DOA*01:01:05. Mortality increased with one (HR, 1.17; 95% CI, 1.0 to 1.36; P = .05) and two (HR, 2.51; 95% CI, 1.41 to 4.45; P = .002) DOA*01:01:05 alleles. HLA-DOA*01:01:05 was a proxy for HLA-DRB1 alleles encoding FEY (P < 10E-15) and FDH (P < 10E-15) amino acid substitutions at residues 26/28/30 that influence HLA-DR
β peptide repertoire. FEY- and FDH-positive alleles were positively associated with rs429916A (P < 10E-15); FDY-positive alleles were negatively associated. Mortality was increased with FEY (HR, 1.66; 95% CI, 1.29 to 2.13; P = .00008) and FDH (HR, 1.40; 95% CI, 1.02 to 1.93; P = .04), whereas FDY was protective (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). Of the three candidate motifs, FEY was validated as the susceptibility determinant for mortality (HR, 1.29; 95% CI, 1.00 to 1.67; P = .05). Although FEY was found frequently among African and Hispanic Americans, it increased mortality independently of ancestry.
Conclusion
:
Patient germline HLA-DRB1 alleles that encode amino acid substitutions that influence the peptide repertoire of HLA-DRβ predispose to increased death after transplantation. Patient germline variation informs transplantation outcomes across US populations and may provide a means to reduce risks for high-risk patients through pretransplantation screening and evaluation.
Journal of Clinical Oncology , résumé, 2017