Genetic risk factors and COVID-19 severity in Brazil: results from BRACOVID study.

The coronavirus disease 2019 (COVID-19) pandemic has changed the paradigms for disease surveillance and rapid deployment of scientific-based evidence for understanding disease biology, susceptibility and treatment. We have organized a large-scale genome-wide association study (GWAS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals in Sao Paulo, Brazil, one of the most affected areas of the pandemic in the country, itself one of the most affected in the world. Here, we present the results of the initial analysis in the first 5233 participants of the BRACOVID study. We have conducted a GWAS for COVID-19 hospitalization enrolling 3533 cases (hospitalized COVID-19 participants) and 1700 controls (non-hospitalized COVID-19 participants). Models were adjusted by age, sex and the 4 first principal components. A meta-analysis was also conducted merging BRACOVID hospitalization data with the Human Genetic Initiative (HGI) Consortia results. BRACOVID results validated most loci previously identified in the HGI meta-analysis. In addition, no significant heterogeneity according to ancestral group within the Brazilian population was observed for the two most important COVID-19 severity associated loci: 3p21.31 and Chr21 near IFNAR2. Using only data provided by BRACOVID, a new genome-wide significant locus was identified on Chr1 near the genes DSTYK and RBBP5. The associated haplotype has also been previously associated with a number of blood cell related traits and might play a role in modulating the immune response in COVID-19 cases.

Impact of HLA-G +3142C>G on the development of antibodies to blood group systems other than the Rh and Kell among sensitized patients with sickle cell disease.

BACKGROUND: Patients' inflammatory history is an important factor underlying red blood cell (RBC) alloimmunization, which is a frequent transfusion complication among individuals with sickle cell disease (SCD). HLA-G has been associated with different inflammatory and auto - immune diseases. Our goal was to verify whether the HLA-G + 3142 C>G and 14-bp Ins/Del variations are associated with RBC antibody development among SCD patients. METHODS: This was a single-center case-control study. SCD patients were randomly selected for the study and divided into two groups: 'Alloimmunized' and 'Nonalloimmunized' depending on the presence of irregular antibodies. The 'Alloimmunized'group was further divided into two subgroups according to the presence of only antibodies against the Rh and Kell blood group systems or the existence of antibodies to antigens of the other blood group systems. RESULTS: A total of 213 patients were included in the study (110 alloimmunized and 103 non-alloimmunized). The 'Alloimmunized' and 'Non-alloimmunized' groups did not differ statistically regarding the HLA-G + 14 bp Ins/Del ( p = 0.494) and + 3142 C>G ( p = 0.334). Individuals who had only antibodies against the Rh and Kell antigens had a frequency of HLA-G + 3142GG genotype almost twice as high compared to the groupwith antibodies against less immunogenic antigens ( p = 0.043). CONCLUSIONS: The genotype frequency of HLA-G + 3142 C>G differs among alloimmunized SCD patients, depending on the presence of antibodies against low immunogenic RBC antigens. This highlights a possible role played by the HLA-G molecule in the RBC alloimmunization process.

Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program.

BACKGROUND: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data. STUDY DESIGN AND METHODS: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. RESULTS: In SLC14A1, variants included four encoding a weak Jka phenotype and five null alleles (JKnull ). JKA*01N.09 was the most common JKnull . One possible JKnull mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fyx (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting Kmod phenotype, all in heterozygosity. CONCLUSIONS: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.

Reduced volume of red blood cell priming is safe for pediatric patients undergoing therapeutic plasma exchange.

RATIONAL: Therapeutic Plasma Exchange (TPE) procedures in pediatric patients are challenging due to the large extracorporeal volume of the cell separators, which were designed for adults. Red blood cell (RBC) priming is an alternative for overpassing the risks of hypovolemia, but data referring to the volume of packed RBCs to be infused are yet incomplete. Restricting the volume of RBC priming may potentially be associated with less transfusion reactions. GOAL: To determine the safety of administering a reduced volume of RBC priming for pediatric patients undergoing TPE, in comparison to the standard volume recommended by the cell separators' manufacturers. METHODS: This was a case-control study which enrolled 15 pediatric patients undergoing TPE and weighting more than 10Kg. The TPE procedures (n = 406) were divided in two groups: 1) Group1: TPE with ≤150 mL of packed RBC priming and 2) Group2: TPE with 150-250 mL of RBC priming. Groups were compared in terms of hemoglobin / hematocrit and occurrence of adverse reactions. RESULTS: Group1 and Group2 did not differ significantly in relation to pre- and post-TPE hemoglobin (Hb) levels (p = 0.19 and p = 0.18, respectively). The Δ Hb (Hb pre-TPE - Hb post-TPE) was also not statistically different between the groups. The number of adverse reactions was significantly higher in Group 2 in relation to Group 1 (p = 0.01). The number of allergic reactions was also higher in Group 2 (p = 0.06). CONCLUSIONS: Restricting the volume of RBC priming to less than 150 mL is safe for pediatric patients weighting more than 10Kg and associated with lower rates of transfusion-related adverse reactions.

FcγR2B B2.4 haplotype predicts increased risk of red blood cell alloimmunization in sickle cell disease patients.

BACKGROUND: Red blood cell (RBC) alloimmunization is an important transfusion complication which is prevalent among sickle cell disease (SCD) patients. Autoimmune diseases are a known risk factor for RBC alloimmunization, suggesting that autoimmunity and post-transfusion alloantibody development occur through similar physiopathological pathways. Polymorphisms in the FcγR2B gene have already been associated with several autoimmune disorders and hypothetically could be associated with RBC alloimmunization. Our goal was to evaluate if important polymorphisms of FcγR2B have an impact on the risk of RBC alloimmunization among SCD patients. STUDY DESIGN AND METHODS: This was a case-control study in which alloimmunized and non-alloimmunized SCD patients were compared in terms of the genotype frequency of the FcγR2B polymorphisms -386G/C, -120 T/A, and 695C/T, genotyped through direct Sanger sequencing. RESULTS: A total of 237 patients met the eligibility criteria, 120 cases (alloimmunized) and 117 controls (non-alloimmunized). RBC alloimmunization was associated with female sex (p < 0.001), lifetime number of RBC units transfused (p = 0.002) and 120 T/A FcγR2B genotype (p = 0.031). The FcγR2B promoter region haplotype 2B.4 (386C120A) was positively associated with RBC alloimunization (p = 0.045). The logistic regression (LR) model identified female sex (OR 10.03, CI 95% 5.16-19.49; p < 0.001) and FcγR2B 2B.4 haplotype (OR 4.55, CI95% 1.1118.65; p = 0.035) as independent predictors of RBC alloimmunization in SCD patients. CONCLUSION: SCD patients with the FcγR2B 2B.4 haplotype had over a fourfold higher risk for RBC alloimmunization. This highlights the role played by FcγR2B on RBC alloimmunization and may be helpful in identifying the immune responders.

Weak D types 38 and 11: determination of frequencies in a Brazilian population and validation of an easy molecular assay for detection.

CONCLUSIONS: Recent evidence shows that, among Brazilians, the distribution of weak D types significantly differs from that represented in people of European descent, with a high percentage of weak D types 38 and 11. Our goal was to determine the population frequencies of weak D types 38 and 11 in a Brazilian population and to validate a molecular approach to identify these two variants. Blood donors were sequentially enrolled in the study in a 5-year period. Donors with serologic weak D phenotype had the RHD coding region sequenced. The frequencies of weak D type 38 and weak D type 11 (CDe-associated) were calculated. Two allele-specific-polymerase chain reaction (AS-PCR) assays were designed to detect RHD*weak D type 38 and RHD*weak partial 11 and were validated with samples positive and negative for these two variants, respectively. A total of 618,542 donors were enrolled, of which 265 presented with a serologic weak D phenotype. When considering all donors evaluated, the frequencies of weak D types 38 and 11 were 0.013 and 0.002 percent, respectively. In the subgroup of donors with a serologic weak D phenotype, the frequencies of weak D types 38 and 11 were 30.2 and 4.9 percent, respectively. The two proposed AS-PCR assays for detection of RHD*weak D type 38 and RHD*weak partial 11 showed 100 percent accuracy. The frequencies of weak D types 38 and 11 among Brazilians are high compared to that previously described for other populations. The AS-PCR assays to detect RHD*weak D type 38 and RHD*weak partial 11 represent potentially helpful tools for investigating Brazilian individuals with these weak D phenotypes.

A Toll-like receptor 2 genetic variant modulates occurrence of bacterial infections in patients with sickle cell disease.

Despite adequate immunization and penicillin prophylaxis, bacterial infections remain a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). Besides hyposplenism, inflammatory and genetic factors might modulate their susceptibility to bacterial infections. We performed a candidate gene association of single nucleotide polymorphisms (SNPs) located in Toll-like receptor (TLR) genes, encoding prominent molecules for innate immune responses, with the occurrence of bacterial infections in patients with SCD. A cohort followed in centres in Brazil, France and Senegal (n = 430) was divided in two groups: patients who presented at least one episode of bacterial infection (n = 235) and patients who never had bacterial infections (n = 195). There were no differences in gender or age distribution among the groups. The frequency of the TLR2 rs4696480 TA genotype was significantly lower in the infected group (50% vs. 67%, odds ratio [OR] = 0·50, 95% confidence interval [CI] 0·34-0·75, P < 0·001), and the TT genotype was significantly higher in the infected group (15% vs. 5%, OR = 3·18, 95% CI 1·53-6·61, P < 0·001). Previous reports demonstrated higher secretion of inflammatory factors in cells from AA individuals, lower occurrence and severity of immune diseases in T carriers. The rs4696480 TA genotype might stand between deleterious effects of over inflammatory response (AA genotype) and inefficient responses (TT genotype) to infectious agents in SCD settings.

Diversity of RH and transfusion support in Brazilian sickle cell disease patients with unexplained Rh antibodies.

BACKGROUND: Genetic diversity in the RH genes among sickle cell disease (SCD) patients is well described but not yet extensively explored in populations of racially diverse origin. Transfusion support is complicated in patients who develop unexpected Rh antibodies. Our goal was to describe RH variation in a large cohort of Brazilian SCD patients exhibiting unexpected Rh antibodies (antibodies against RH antigens to which the patient is phenotypically positive) and to evaluate the impact of using the patient's RH genotype to guide transfusion support. STUDY DESIGN AND METHODS: Patients within the Recipient Epidemiology and Evaluation Donor Study (REDS)-III Brazil SCD cohort with unexpected Rh antibodies were selected for study. RHD and RHCE exons and flanking introns were sequenced by targeted next-generation sequencing. RESULTS: Fifty-four patients with 64 unexplained Rh antibodies were studied. The majority could not be definitively classified as auto- or alloantibodies using serologic methods. The most common altered RH were RHD*DIIIa and RHD*DAR (RHD locus) and RHCE*ce48C, RHCE*ce733G, and RHCE*ceS (RHCE locus). In 53.1% of the cases (34/64), patients demonstrated only conventional alleles encoding the target antigen: five of 12 anti-D (41.7%), 10 of 12 anti-C (83.3%), 18 of 38 anti-e (47.4%), and one of one anti-E (100%). CONCLUSION: RHD variation in this SCD cohort differs from that reported for African Americans, with increased prevalence of RHD*DAR and underrepresentation of the DAU cluster. Many unexplained Rh antibodies were found in patients with conventional RH allele(s) only. RH genotyping was useful to guide transfusion to determine which patients could potentially benefit from receiving RH genotyped donor units.

Defining the clinical relevance of red blood cell autoantibodies by Monocyte Monolayer Assay.

BACKGROUND: The Monocyte Monolayer Assay (MMA) is an in vitro simulation of red blood cell (RBC) alloantibody behavior. It has been classically applied to predict the risks of post-transfusion hemolytic reactions when transfusing incompatible RBC units. Quantifying erythrophagocytosis by MMA may be an interesting option for situations where there is doubt whether a RBC autoantibody is mediating significant hemolysis. Here, we present three situations involving RBC autoantibodies in which the MMA was decisive for clarifying the diagnosis and choosing the best clinical treatment. CASE REPORT: Case 1. Pregnant patient with severely anemic fetus exhibited warm autoantibody without signs of hemolysis. MMA revealed 30% of monocyte index (MI) highlighting that fetal hemolysis was caused by maternal autoantibody. Prednisone was prescribed with fetal clinical improvement. Cases 2 and 3. Two patients with the diagnosis of mixed auto-immune hemolytic anemia and poor response to corticosteroids were evaluated using MMA. The resulting MI was less than 10% in both cases, suggesting that the cold-agglutinin rather than the warm auto-IgG was responsible for overt hemolysis. Treatment with rituximab was begun, with good clinical response. CONCLUSION: MMA can be used to evaluate the ability of RBC autoantibodies to mediate overt hemolysis. It can be especially useful to determine the role played by cold and warm auto-antibodies in mixed auto-immune hemolytic disease, helping to define the best treatment option.

High frequency of variant RHD genotypes among donors and patients of mixed origin with serologic weak-D phenotype.

BACKGROUND: The current transfusion policy recommended for individuals with serologic weak-D phenotype is based on data derived from European-descent populations. Data referring to the distribution of RH alleles underlying weak-D phenotype among people of mixed origin are yet incomplete, and the applicability of European-based transfusion guidelines to this specific population is questionable. GOAL: To evaluate the distribution of RHD variant genotype among individuals with serologic weak-D phenotype of both African and European descent. METHODS: Donors and patients of mixed origin and with serologic weak-D phenotype were selected for the study. They were investigated using conventional RHD-PCR assays and RHD whole-coding region direct sequencing. RESULTS: One hundred and six donors and 58 patients were included. There were 47 donors and 29 patients with partial-D genotype (47/106, 44.3%, and 29/58, 50%, respectively). RHD*DAR and RHD*weak D type 38 represented the most common altered RHD alleles among donors (joint frequency of 39.6%), while weak D types 1-3 accounted for 10.4% of the total D variant samples. RHD*DAR was the most common allele identified in the patient group (frequency of 31%), and weak D types 1-3 represented 29.3% of the total. CONCLUSION: The frequency of partial D among mixed individuals with serologic weak-D phenotype is high. They should be managed as D-negative patients until molecular tests are complete.

High-throughput strategy for molecular identification of Vel- blood donors employing nucleic acids extracted from plasma pools used for viral nucleic acid test screening.

BACKGROUND: Serologic methods to determine the Vel- phenotype require the use of rare human antisera and do not allow for many samples to be tested simultaneously, which limits their application as a tool to search for rare donors. This study developed a low-cost molecular screening strategy using real-time polymerase chain reaction (PCR) and DNA, extracted from plasma pools for viral nucleic acid test (NAT) screening, to identify Vel- and Vel+(W) donors. STUDY DESIGN AND METHODS: A total of 4680 blood donors from the Brazilian southeast region were genotyped through real-time PCR targeting the 17-nucleotide (c.64_80del) deletion in the SMIM1 gene, which determines the Vel- phenotype, by using remaining nucleic acid from plasma pools of six donors, routinely discarded after the release of viral NAT results. RESULTS: Twenty pools tested reactive and individual testing of samples from reactive pools identified 19 heterozygous donors with the SMIM1*64_80del deletion (0.40%) and one homozygous donor (0.02%). Fourteen of the 19 donors were confirmed as Vel- or Vel+(W) using anti-Vel human antiserum. CONCLUSION: The DNA pool genotyping strategy using real-time PCR designed to detect the deletion in the SMIM1 gene proved effective and accurate in identifying donors with the Vel- and Vel+(W) phenotypes. The fact that remaining nucleic acid from routine viral NAT screening was used makes this technique economically attractive and definitely superior to the serologic techniques available to search for this rare phenotype.

Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy.

Chagas disease is a tropical zoonosis caused by Trypanosoma cruzi. After infection, the host present an acute phase, usually asymptomatic, in which an extensive parasite proliferation and intense innate immune activity occurs, followed by a chronic phase, characterized by low parasitemia and development of specific immunity. Most individuals in the chronic phase remain without symptoms or organ damage, a state called indeterminate IND form. However, 20 to 40% of individuals develop cardiac or gastrointestinal complications at any time in life. Cardiomyocytes have an important role in the development of Chronic Chagas Cardiomyopathy (CCC) due to transcriptional and metabolic alterations that are crucial for the parasite survival and replication. However, it still not clear why some infected individuals progress to a cardiomyopathy phase, while others remain asymptomatic. In this work, we used hiPSCs-derived cardiomyocytes (hiPSC-CM) to investigate patterns of infection, proliferation and transcriptional response in IND and CCC patients. Our data show that T. cruzi infection and proliferation efficiency do not differ significantly in PBMCs and hiPSC-CM from both groups. However, RNA-seq analysis in hiPSC-CM infected for 24 hours showed a significantly different transcriptional response to the parasite in cells from IND or CCC patients. Cardiomyocytes from IND showed significant differences in the expression of genes related to antigen processing and presentation, as well as, immune co-stimulatory molecules. Furthermore, the downregulation of collagen production genes and extracellular matrix components was significantly different in these cells. Cardiomyocytes from CCC, in turn, showed increased expression of mTORC1 pathway and unfolded protein response genes, both associated to increased intracellular ROS production. These data point to a differential pattern of response, determined by baseline genetic differences between groups, which may have an impact on the development of a chronic outcome with or without the presentation of cardiac symptoms.

Clonal hematopoiesis in sickle cell disease.

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH.

Rare genetic variants explain missing heritability in smoking.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the TLR2 rs4696480 TA, TLR2 rs3804099 CC, and HLA-G, rs9380142 AA genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G rs9380142 G allele increased the risk of cholelithiasis (AG vs. AA, OR 1.57, 95%CI 1.16-2.15; GG vs. AA, OR 2.47, 95%CI 1.34-4.64; P = 0.02). For SNPs located in the NKG2D loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, rs2246809 (AA vs. GG: OR 0.22, 95%CI 0.09-0.50; AG vs. GG: OR 0.47, 95%CI 0.31-0.71; P = 0.004, for patients of same origin), rs2617160 (AT vs. TT: OR 0.67, 95%CI 0.48-0.92; AA vs. TT: OR 0.45, 95%CI 0.23-0.84; P = 0.04), and rs2617169 (AA vs. TT: OR 0.33, 95%CI 0.13-0.82; AT vs. TT: OR 0.58, 95%CI 0.36-0.91, P = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management.