Common Hereditary Variants of the APOE Gene and Posttransplant Outcome in Acute Myeloid Leukemia.

Abstract

Apolipoprotein E (APOE) has multiple functions in metabolism and immunoregulation. Its common germline variants APOE2, APOE3 and APOE4 give rise to three functionally distinct gene products. Previous studies reported yin-yang roles of APOE2 and APOE4 in immunological processes, but their effects in hematopoietic stem cell transplantation (HSCT) have never been studied. We performed APOE genotyping in two contemporary cohorts of 348 and 447 patients with acute myeloid leukemia (AML) who had received allogeneic HSCT and evaluated associations of recipient and donor APOE genetic variation with posttransplant outcome. Patients who carried at least one APOE2 allele had a higher risk of posttransplant death compared to APOE4 carriers in the discovery (hazard ratio [HR] 2.09, P = .024) and validation cohorts (HR 1.96, P = .040). Detrimental APOE2 effects were driven by an increased risk of severe chronic graft-versus-host disease (GvHD; HRadj 1.85, P = .034) and non-relapse death (HRadj 1.72, P = .044). In non-APOE2 recipients, transplantation of an APOE2-positive allograft was associated with an increased incidence of grade III-IV acute GvHD (HRadj 2.82, P = .012) and severe chronic GvHD (HRadj 2.54, P = .022) compared to APOE2-negative grafts. In summary, the APOE2 allele, typically considered a longevity gene in the general population, was associated with a higher risk of acute GvHD (HRadj 2.75, P = .002), chronic GvHD (HRadj 2.57, P = .001), and posttransplant mortality (HRadj 1.79, P = .004), when present either in the host or transplanted from the donor.