The second most significant locus for class I alloantibodies is on chr12, just 5 of the E2F7 gene (Figure 2B), although these SNPs do not exceed genome-wide significance (rs7487338; P= 2.4 10?7; OR = 0.41[0.29C0.57]), and this result will require additional replication. function of NXPH2, although gene family members have been shown to impact immunity. SNPs in the E2F7 gene, a transcription factor related to cell-cycle control and cellular proliferation, also approached genome-wide significance (P= 2.5 10?7). Conclusion Further work to extend the GWAS approach and to characterize variants in NXPH2 and E2F7 in the context of alloantibody formation is warranted. Introduction It has been appreciated for over 50 years that pregnancy can lead to alloimmunization, (1) and high titer HLA antibodies can persist for decades after pregnancy (2). Successive pregnancies carry further risk for antibody formation. Using sensitive assays for detection of HLA antibodies, it was shown that ~10% of women are alloimmunized after one pregnancy, and this rises to ~30% of women after four or more pregnancies (3). Alloimmunization is also a significant clinical problem in transfusion medicine (4C17). While this is usually not problematic for recipients who experience limited exposures to allogeneic blood products, alloimmunization is usually a concern for those who depend on regular HVH3 platelet or RBC transfusions, including patients with hematological malignancies, myelodysplastic disease, or patients with sickle cell disease and other inherited hemoglobin disorders (RBC dependent). Currently, leukoreduction of transfusion products (3,5,16), prophylactic transfusion of antigen matched red blood cell models (5,18,19), and frequent laboratory monitoring for new antibody formation with subsequent use of cross-match compatible blood components (5,9,18), are the only tools available to manage transfusion therapy in patients with antibodies to reddish blood cell, 2C-I HCl HLA, or platelet antigens. Both prior pregnancy and blood transfusion were identified as major contributors to HLA alloimmunization for subjects awaiting kidney transplant (20). The presence of HLA antibodies is usually associated with increased risk for rejection and graft failure, both acutely (21) and over the lifetime of the graft (22). Alloimmunization — whether to RBC, platelet-specific, or HLA antigens, depending on the type of blood product received or other exposure — occurs in roughly one-third of blood recipients in the absence of full or partial RBC antigen matching or leukoreduction (5C7,14,19,23). This regularity in the alloimmunization rates among individuals, regardless of the type of exposure (e.g., RBC, HLA or platelet-antigen antibodies following transfusions, or even HLA alloimmunization following pregnancy), together with indications of overlap among the subpopulations vulnerable to alloimmunization across these numerous exposures, suggests the presence of host susceptibility factors that are likely to be in part genetically decided (6,8,12,24). Comparable conclusions were reached with a mathematical model based on a database of thousands of transfusion recipients in diverse patient populations (23,25,26). Data from your transplantation setting suggest that women who are not alloimmunized during pregnancy are less likely to develop donor-specific antibodies after transplantation (27). Recent technological developments (i.e., high-throughput, genome-wide single nucleotide polymorphism (SNP) genotyping using commercial arrays) enable the comprehensive search for genetic variation associated with differing risks of alloimmunization (28). 2C-I HCl Here we statement the results of a GWAS including 752 alloantibody positive and 2C-I HCl 753 alloantibody unfavorable, previously pregnant female blood donors who had been enrolled in the Leukocyte Antibody Prevalence Study (LAPS). We found associations exceeding genome-wide significance for SNPs within the NXPH2 gene and close to genome-wide significance for the E2F7 gene. Materials and Methods Study Subjects Subjects were drawn from your previously conducted Retrovirus Epidemiology Donor Study-II (Reds-II) LAPS cohort (3,17), a multi-center cross-sectional study designed to measure the prevalence and laboratory characteristics of HLA and neutrophil antibodies in blood donors with and without a history of known allogeneic exposures through blood transfusion or pregnancy. The LAPS protocol involved a questionnaire for enrolled donors that characterized donors for transfusion and pregnancy history, in addition to routine demographic variables such as age, race-ethnicity and gender. Donors gave specific consent to studies of genetic factors that may be involved in immune reactions to pregnancy and transfusion, including alloimmunization. Each subject in 2C-I HCl the LAPS repository has been tested for class I and II HLA allo-antibodies, and classified.