ABO blood groups as determinants to patient outcomes in SARS-CoV-2

Background: Blood group antigens are present on the red blood cell surface. O, A, and B are the major blood groups. A, B, AB, and A1 are the antigens. An ample amount of research supports the close association of blood groups with diseases. A new school of thought and finding seems to be indicating that certain blood groups are more susceptible to the COVID-19 infection in comparison to others. Current evidence suggests that SARS-CoV-2 positive cases are more prevalent in individuals with blood group A as compared to those with blood group O. This finding, however, was only relevant for the Rh (+ve) positive blood types. Genetic association reveals that the ABO blood group locus and a chromosome 3 gene cluster are associated with severe acute respiratory syndrome in coronavirus (SARS-CoV-2) respiratory failure patents. This was found in an Italian- Spanish genome-wide association analysis. Various associations between the patients' blood groups when comparing the data with that of physiologically healthy individuals from the same geographical region helped to get a clear comparative picture. Associations that were cross-replicating in nature were determined at chromosome 3p21.31 and chromosome 9q34. The association at chromosome 9q34 was identified at the ABO blood group locus. The difference in the susceptibility could be correlated to the circulating anti‐A antibodies, which inhibit or interfere with the virus-cell adhesion process. Conclusion: It is evident that the research conducted to date is supportive and does suggest that humans of the Blood group O are less likely to be infected in the COVID-19 pandemic as when compared to other blood groups. The SARS-CoV-2 situation is evolving rapidly, discoveries and anomalies are being reported daily. Therefore, it is advised that more definitive and consolidatory research is to be conducted to further elucidate the underlying mechanism of action for the protection in blood group O.

Variants in ADAMTS13 and Smoking Contribute to Plasma ADAMTS13 Level Variation

Homeostatic processing of von Willebrand factor (VWF) in the circulation relies on proteolysis of ultra-large VWF (ULVWF) multimers by the metalloprotease ADAMTS13. Deficiency in ADAMTS13 results in Thrombotic Thrombocytopenic Purpura (TTP) due to the accumulation of thrombogenic ULVWF. ADAMTS13 is secreted into the circulation in its active form and has no known inhibitor. Regulation of ADAMTS13 activity occurs in part through plasma ADAMTS13 levels and by the hemodynamic exposure of the scissile bond in VWF. To identify the genetic determinants of ADAMTS13 levels we performed genome-wide association studies (GWAS) and linkage analysis in two independent cohorts of young healthy individuals. This study recruited 3206 young healthy individuals of European descent who participated in the Genes and Blood Clotting Study (GABC, n=940) and the Trinity Student Study (TSS, n=2266). All subjects provided written informed consent and all genotyping and phenotyping was performed on de-identified samples. Details of the genotyping and data cleaning process for these cohorts were previously described. (Desch KC et al. PNAS 2013, 110:588-593) ADAMTS13 levels were measured by a custom AlphaLISA (Perkin-Elmer, Waltham, MA) assay using polyclonal anti-ADAMTS13 antibodies (a gift from X. Long Zheng, University of Pennsylvania). In GABC, the median ADAMTS13 levels were 115.4 IU/dL and demonstrated a 2.0-fold variation between the 5th and 95th percentiles. Heritability of ADAMTS13 levels was estimated at 77% in GABC and 43% in the TSS. ADAMTS13 levels were associated smoking in both cohorts and was associated with an 8.9% increase in levels of ADAMTS13 (P < 1.5E-11, GABC). GWAS identified 10 SNPs in GABC and 33 SNPs in TSS that were significantly associated with ADAMTS13 levels (P<1.0E-8), Figure 1. In both cohorts, significant signals were located at the ADAMTS13 gene on chromosome 9q34. The top SNP association signal in GABC was at rs2073933 (P < 4.48E-12) and the minor allele was associated with a 6.9% decrease in ADAMTS13 levels. In the TSS study this SNP was also significant (P < 2.37E-42) and associated with a 5.2% decrease in ADAMTS13 levels. In both GWAS studies, no SNPs remained significant after the top ADAMTS13 SNP was used as a covariate. Linkage analysis, which maps genomic regions where allele sharing patterns in families correlate to ADAMTS13 levels, identified 2 regions with LOD scores greater than 3. The first signal was on chromosome 9q34, including ADAMTS13 (LOD 4.12) and the second was on chromosome 5p13 including EGFLAM (LOD 3.08). Although ABO mediated glycosylation patterns affect VWF clearance rates, no signal in ABO was detected in our multiple association studies suggesting that the common ABO haplotypes are not associated with ADAMTS13 levels. Although other mutations tagged by the significantly associated SNPs cannot be excluded, a potential candidate mutation (rs2301612, Q448E) was identified in ADAMTS13 and may be responsible for the decrease in ADAMTS13 levels through alteration of synthesis/secretion or plasma clearance rates. Aditionally, linkage analysis confirmed the chromosome 9q34 signal and identified a region on chromosome 5p13 that was not detected by GWAS. This finding suggests that rare variants in this genomic region also contribute to ADAMTS13 levels. The identification of mutations that determine normal ADAMTS13 variation may lead to a better understanding of the genetic risk for TTP and mechanisms of von Willebrand Factor homeostasis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

SET-NUP214 Fusion Gene at Chromosome 9q34 Contributed to the Development of Not Only T-ALL, but Also Primary and Secondary AML.

Abstract 4696 SET-NUP214 rearrangement at chromosome 9q34 is an extremely rare recurrent cryptic deletion resulting from del(9)(q34.11q34.13) mainly found in T-cell acute lymphoblastic leukemia (T-ALL). A multiplex RT-PCR system (HemaVision; DNA Technology) covering 28 leukemic fusion transcripts was applied to 271 bone marrow (BM) samples obtained from acute leukemia patients at initial diagnosis to investigate new pathophysiologic role of SET-NUP214 fusion gene. Out of 271 samples, we identified three cases (1.1%) harboring SET-NUP214 rearrangement – each case of adult T-ALL, pediatric acute myeloid leukemia (AML) from chronic myeloid leukemia (CML) and adult de novo AML with minimal differentiation (M0). Adult T-ALL occurred in 38-year-old man presented with dizziness and hepatomegaly. Conventional cytogenetic study disclosed normal karyotype and existence of SET-NUP214 fusion gene generated by del(9)(q34.11q34.13) was confirmed by RT-PCR, FISH and direct sequencing. Hematological remission was achieved after treatment of induction chemotherapy but during 7 months follow-up, SET-NUP214 fusion gene was steadily detected by RT-PCR. 13-year-old female with AML M0 converted from CML after treatment of imatinib for 2 months was the second case. Leukemic cells showed negative myeloperoxidase (MPO) and sudan-black B (SBB) staining, positive reaction against CD13, CD33, CD117 and MPO monoclonal antibodies by flowcytometry-based immunophenotyping. Major BCR-ABL1 rearrangement and SET-NUP214 fusion genes were simultaneously detected by RT-PCR, FISH and direct sequencing. She died at 38 days after diagnosis during the chemotherapy. The fusion protein contributed to the leukemogenesis by promoting expression of HOXA cluster genes. Last case was a de novo AML M0 in 39-year-old male. Cytochemical stains of leukemic cells on MPO and SBB were negative and immunophenotyping studies were positive for CD34, HLA-DR, CD13 and CD33. SET-NUP214 rearrangement was detected by multiplex RT-PCR. After treatment of induction and consolidation chemotherapy, he received allogeneous sibling stem cell transplantation (SCT), then complete chimerism was achieved. In clonclusion, SET-NUP214 rearrangement is associated with the development of not only T-ALL, but also primary and secondary AML via aberrant expression of HOXA cluster genes. Disclosures: No relevant conflicts of interest to declare.

Phenotypic Heterogeneity in Body Fat Distribution in Patients with Congenital Generalized Lipodystrophy Caused by Mutations in the AGPAT2 or Seipin Genes

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. Recently, we reported mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene in CGL pedigrees linked to chromosome 9q34 (CGL1 subtype), and mutations in the Seipin gene were reported in pedigrees linked to chromosome 11q13 (CGL2 subtype). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. We conclude that CGL patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene.