Selecting the Optimal Unrelated Hematopoietic Stem Cell Transplant Donor for Relapse Prevention in Acute Myeloid Leukemia

Introduction/Background Hematopoietic cell transplantation (HCT) provides a cure for patients with acute myeloid leukemia. Natural killer cells (NK) play an important role in graft versus leukemia (GVL) effect after HCT, through killer immunoglobulin-like receptor (KIR) interaction with HLA ligands. This study is undertaken to validate our previously published mathematical model accounting for the KIR-KIRL interactions in a post HCT setting. Methods Retrospective data were obtained from the Center for International Blood and Marrow Transplant Registry for 2317 donor recipient pairs (DRP) who underwent 7/8 or 8/8 HLA allelic matched unrelated donor (URD) HCT for AML. KIR-HLA interaction scores were calculated by summing interaction values as previously described (Krieger et. Al BBMT 2019). Results Relapse risk was significantly reduced with donor-recipient pairs (DRP) with the higher inhibitory KIR-KIRL interaction and missing KIRL scores, Cox prop hazard, HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. The inhibitory KIR-KIRL interaction score components were then summed to give an IM-KIR score; IM KIR score =5 was also associated with a lower relapse risk, HR 0.8 (P=0.003). Subset analysis of 8/8 HLA matched patients showed further relapse reduction HR 0.75 (P=0.001); those patients with IM-KIR=5 donors who received ATG for in vivo T cell depletion (N=730) showed a 39% relapse reduction (HR 0.61, P=0.001) with a trend toward improved RFS, HR 0.84 (p=0.11). The use of ATG was shown to modify the effect of IM KIR score in interaction analysis (p=0.049), suggesting higher NK cell magnitude of KIR-KIRL interaction compensates for the general increase of relapse who receive in vivo T cell depletion. Conclusion This large international study confirms that unrelated DRPs with high iKIR and mKIR scores, as well as a combined IM-KIR scores confer significant relapse protection after MUD HCT, indicating that donors with a higher iKIR content may be considered optimal for URD HCT recipients with AML

The Association Between Urinary Genistein Levels and Mortality Among Adults in the United States

BackgroundCurrent research on the relationship between phytoestrogens and mortality has been inconclusive. We explored the relationship between genistein, a phytoestrogen, and mortality in a large cohort representative of the United States population.Methods: Data were analyzed from the National Health and Nutrition Examination Survey (NHANES) from 1999–2010. Normalized urinary genistein (nUG) was analyzed as a log-transformed continuous variable and in quartiles. Mortality data were obtained from the National Death Index and matched to the NHANES participants. Survival analyses were conducted using the Kaplan-Meier analysis. Cox proportional hazard models were constructed for all-cause and cause-specific mortality without and with adjustment for potential confounding variables.Results: Of 11,497 participants, 944 died during the 64,443 person-years follow-up. The all-cause mortality rate was significantly lower in the lowest quartile compared to the highest quartile (incidence rate ratio = 2.14, 95%CI = 1.76 to 2.60). Compared to the lowest quartile, the highest quartile had significantly higher adjusted all-cause (HR = 1.57, 95%CI = 1.23 to 2.00), cardiovascular (HR = 1.67, 95%CI = 1.04 to 2.68), and other-cause (HR = 1.85, 95%CI = 1.33 to 2.57) mortality.Conclusion: We found that high urinary genistein levels were associated with increased risk of all-cause, cardiovascular, and other-cause mortality. This is contrary to popular opinion on the health benefits of genistein and needs further research

Association of Anti-Mullerian Hormone with C-Reactive Protein in Men

While serum anti-mullerian hormone (AMH) levels are inversely associated with all-cause mortality in men, the underlying mechanisms are unclear. Elevated levels of inflammation, also associated with all-cause mortality, and may be the link between AMH and mortality. Hence, we examined the association of AMH with serum c-reactive protein (CRP), a biomarker of inflammation, in men. We included men ≥20 years from the National Health and Nutrition Examination Survey (1999–2004). We used survey weight-adjusted linear regression to examine the association between AMH and CRP without and with adjustment for age, race, body mass index (BMI), smoking, hypertension, diabetes, cholesterol, glomerular filtration rate (GFR), testosterone, androstenedione, and sex hormone binding globulin. Of the 949 men, 212 (22%) were elderly, 493 (52%) Caucasian, 254 (27%) current smokers, 100 (10%) diabetics, and 312 (33%) had hypertension. Mean (SD) AMH was 8.4 (7.2) ng/mL and median (IQR) CRP level was 0.17 (3) mg/L. Using linear regression, each 10 ng/mL rise in AMH was associated with 0.09 mg/dL (95%CI = −0.14 to −0.03; p = 0.002) decrease before and 0.08 mg/dL (95%CI = −0.13 to −0.02; p = 0.004) decrease in CRP after adjusting for potential confounders. Similarly, men in the highest quartile of AMH had significantly lower CRP compared to those in the lowest quartile (unadjusted difference = −0.19 mg/dL; 95%CI = −0.31 to −0.06; p = 0.006, adjusted difference = −0.16 mg/dL; 95%CI = −0.3 to −0.01; p = 0.035). We found an independent, robust, and inverse association between CRP and AMH in men. Effect of AMH on mortality may be through amelioration of inflammation

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation

A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans

Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p<5×10−8 of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1×10−9), 7q11 (rs13236689, CD36, p = 2.8×10−9), 10q21 (rs7896518, JMJD1C, p = 2.3×10−12), 11q13 (rs477895, BAD, p = 4.9×10−8), and 20q13 (rs151361, SLMO2, p = 9.4×10−9). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p<5×10−8, two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis

Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network

Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ∼16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E−13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E − 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits

Sex-specific relationship between blood selenium levels and platelet count in a large cohort representative of the United States population

While several small studies have found that selenium deficiency is associated with low platelet counts, they lack generalizability. We used data from the National Health and Nutrition Examination Surveys collected over a 12-year period. We examined the relationship between selenium quartiles and platelet count using survey-weighted linear regression models adjusting for age, sex, race, household income to poverty threshold income, highest education attainment, smoking status, red blood cell folate, and body mass index. Of the 21,764 participants, 51% were females, 23% African Americans, and 25% were >65 years of age. Mean (SD) platelet count was 243(64) 109/L and selenium was 183(32) µg/L. Women had significantly higher platelet count but lower selenium levels than men (258 vs. 227 109/L and 181 vs. 185 µg/L respectively; both P < 0.0001). In adjusted analysis, participants in the highest selenium quartile had 8.0x109/L higher platelet count as compared to those in the lowest selenium quartile (95%CI = 4.1 to 11.9; P < 0.0001). Gender modified the relationship between the two; although there was no difference in women, platelet count was higher in the highest than the lowest selenium quartile in men (interaction p-value = 0.001). These findings highlight the importance of selenium and gender in platelet biology which needs to be explored