Candidate Gene Polymorphisms and Their Association with TCD Velocities in Children with Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 429-429 ◽  
Author(s):  
Abdullah Kutlar ◽  
Donald Brambilla ◽  
Betsy Clair ◽  
Anne Haghighat ◽  
Sule Bakanay ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Sickle Cell Disease ◽  
Candidate Gene ◽  
Sickle Cell ◽  
Gene Polymorphisms ◽  
Large Scale ◽  
Binary Classification ◽  
Conditional Logistic Regression ◽  
Cell Disease ◽  
Stop Trial

Abstract Ischemic stroke occurs in 11% of patients with sickle cell disease (SCD) by age 20. The STOP and STOP-II trials showed that the risk of ischemic stroke increases with Transcranial Doppler (TCD) velocities in major intracranial arteries in children with SCD 2–16 years of age, and that the risk in children with abnormal velocities (>200 cm/sec) can be significantly reduced by prophylactic transfusions. Risk factors for development of high TCD phenotype are not clearly established. In an ancillary study to STOP/STOP-II, we analyzed 28 polymorphisms in 20 candidate genes for association with elevated TCD velocity. DNA was extracted from 130 patients randomized in the STOP trial, all of whom had abnormal TCD velocities, and from 355 patients who were screened for STOP II at 8 participating centers. None of the subjects from either trial had histories of overt stroke when they were screened. Samples from STOP subjects were anonymized according to an IRB-approved plan; informed consent/assent was obtained from subjects screened for the STOP-II trial. Hb phenotype was ascertained by HPLC. High throughput genotyping was performed using the MassARRAY™ System (Sequenom Inc., San Diego, CA) at Mass U. TCD status was classified as normal (<170 cm/sec) or not normal (>170 cm/sec) using the average of all TCDs on each patient, excluding any TCDs obtained after starting transfusion (median: 2 TCD exams, range 1–16). Genotyping results for each SNP were also reduced to a binary classification (mutation present or absent) by combining heterozygous subjects with those homozygous for the mutation. Conditional logistic regression was employed to model the probability of having at least 1copy of the mutant allele as a function of TCD status stratified on age class. Under this approach, the odds ratio (OR) relating TCD status to genotype is assumed to be the same at all ages but the prevalence of abnormal or conditional TCD is allowed to vary with age. Seven SNPs were excluded from analyses: all subjects studied (479) were homozygous for the common allele for 5 SNPs, and only 2 subjects were heterozygous for the minor allele for 2 SNPs. The prevalence of abnormal TCD varied with age; the highest prevalence was found in 8–9 year old subjects. Only one SNP, VCAM G1238C, had a significant OR of 0.6 (p=0.03) suggesting this SNP is protective from high TCD. The same polymorphism was found to be protective from stroke with an OR of 0.3 in a different cohort of patients by Taylor et al (Blood, 100:4303–9, 2002). Several published studies have reported on association of stroke with candidate gene polymorphisms with differing results. This is the first large scale study of the association of abnormal TCD (stroke risk) with genetic polymorphisms. To our knowledge, it is also the first confirmatory genetic association study in SCD and cerebrovascular disease in a different population of subjects. Functional analyses of this polymorphism and association of stroke and candidate gene polymorphisms in this cohort are planned.

scholarly journals PREVALENCE OF HEPATITIS C AMONG EGYPTIAN CHILDREN WITH SICKLE CELL DISEASE AND THE ROLE OF IL28B GENE POLYMORPHISMS IN SPONTANEOUS VIRAL CLEARANCE

2016 ◽  
Vol 8 ◽  
pp. 2016007 ◽  
Author(s):  
Somaia Mohammed Mousa ◽  
Mona Kamal El-Ghamrawy ◽  
Mona Kamal El-Ghamrawy ◽  
Heba Gouda ◽  
Heba Gouda ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gene Polymorphisms ◽  
Hcv Rna ◽  
Spontaneous Clearance ◽  
Cell Disease ◽  
Persistent Viremia ◽  
Egyptian Children ◽  
Hcv Antibody

Background and objectives: Hepatitis C virus (HCV) is a major health problem in Egypt with its prevalence estimated to be 14.7% among general population in 2008. Patients receiving frequent blood transfusions like sickle cell disease (SCD) are more exposed to the risk of acquiring HCV. IL28B gene polymorphisms have been associated with spontaneous HCV clearance. This study aims to determine the prevalence of HCV infection among children with SCD and to study the relation between IL28B gene polymorphisms and spontaneous HCV clearance.Methods: Seventy SCD patients were screened for HCV antibody. HCV positive patients were tested for the level of HCV RNA using quantitative real time PCR. IL28B polymorphisms (rs 12979860 SNP and rs 12980275 SNP) were detected using Taqman QRT-PCR and sequence specific primers PCR respectively. Results: Sixteen patients (23%) were HCV antibody positive, 9 of them (56.3%) had undetectable HCV RNA in serum and 7 (43.7%) had persistent viremia. Genotypes CC/CT/TT of rs12979860 were found in 30 (42.9%), 29 (41.4%) and 11 (15.7%) and rs12980275 AA/AG/GG were found in 8 (11.4%), 59 (84.3%) and 3 (4.3%).  There was no significant difference in the frequency of IL28B (rs 12979860 and rs12980275) genotypes among HCV patients who cleared the virus and those with persistent viremia (p=0.308 and 0.724 respectively). Conclusion: Egyptian SCD patients have high prevalence of HCV. Muti-transfused patients still exposed to a risk of transmission of HCV. IL28B gene polymorphisms are not associated with spontaneous clearance of HCV in this cohort of Egyptian children with SCD.

scholarly journals Ischemic Stroke in Children and Young Adults with Sickle Cell Disease (SCD) in the Post-STOP Era

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 68-68 ◽  
Author(s):  
Janet L. Kwiatkowski ◽  
Julie Kanter ◽  
Heather J. Fullerton ◽  
Jenifer Voeks ◽  
Ellen Debenham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
High Risk ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Stroke Prevention ◽  
Cell Disease ◽  
Clinical Series ◽  
The Mean

Abstract Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event. Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. Disclosures No relevant conflicts of interest to declare.

Abstract P726: Cytochrome B5 Reductase 3 Modifies The Brain-Blood Axis Response To Ischemic Stroke In Mice With Sickle Cell Disease

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Katherine C Wood ◽  
Heidi M Schmidt ◽  
Scott Hahn ◽  
Mehdi Nouraie ◽  
Mara Carreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
African Ancestry ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Wild Type ◽  
Cell Disease ◽  
Cytochrome B5 Reductase

Introduction: Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children. Decreased nitric oxide bioavailability and responsiveness contribute to neurovascular disease. Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reduces oxidized soluble guanylate cyclase heme iron (Fe 3+ --> Fe 2+ ) to preserve nitric oxide signaling. A loss-of-function Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry. Hypothesis: We hypothesized that impaired reductase function of T117S Cyb5R3 exacerbates brain damage after ischemic stroke in SCD. Methods: Bone marrow transplant was used to create male SCD mice with wild type (SS/WT) or T117S (SS/T117S) Cyb5R3. Blood was sampled before and after middle cerebral artery occlusion (55 minutes occlusion, 48 hours reperfusion). Infarct volume (IV) was determined by 2,3,5-triphenyltetrazolium chloride. Intravascular hemolysis and correlation (Pearson’s R) of hematology changes with IV were determined. Baseline Walk-PHaSST (NCT00492531) data were analyzed for stroke occurrence. Results: Brain IV (63 vs 27 cm 3 , P=0.003) and mortality (3/6 vs 0/8) were greater in SS/T117S vs SS/WT. Red blood cells, hemoglobin and hematocrit declined as IV increased. Plasma oxyhemoglobin increased in parallel with IV (r = 0.74, P=0.09). There were different signatures to hematologic changes that occurred with IV in SCD. Relative to wild type, T117S contracted the erythroid compartment (red blood cell: -13% vs 13%, P=0.003; hematocrit: -20% vs 1%, P=0.008; hemoglobin: -18% vs 2%, P=0.007). Mean platelet volume correlated with IV in SS/T117S (r = 0.87, P=0.06), while the inverse occurred in SS/WT (r = -0.63, P=0.09) Monocytes increased in parallel with IV in SS/T117S (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT (r = -0.77, P=0.04). WalkPHaSST participants with T117S Cyb5R3 self-reported more ischemic stroke (7.4% vs 5.1%) relative to wild type. Conclusion: Cyb5R3 is an important modifier of the evolution and outcome of ischemic brain injury in SCD and its hematologic consequences. Our findings indicate a bidirectional relationship between stroke and anemia in SCD that may axially turn on Cyb5R3 activity.

scholarly journals Klotho gene polymorphisms and their association with sickle cell disease phenotypes

2015 ◽  
Vol 37 (4) ◽  
pp. 275-276 ◽  
Author(s):  
Claudia R. Lustosa Souza ◽  
Marily M. Azevedo Shimmoto ◽  
Perla Vicari ◽  
Grazielle Mecabo ◽  
Martha Mariana Arruda ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gene Polymorphisms ◽  
Cell Disease ◽  
Disease Phenotypes ◽  
Klotho Gene

scholarly journals Integration of Mobile Health Into Sickle Cell Disease Care to Increase Hydroxyurea Utilization: Protocol for an Efficacy and Implementation Study

10.2196/16319 ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. e16319
Author(s):  
Jane S Hankins ◽  
Nirmish Shah ◽  
Lisa DiMartino ◽  
Donald Brambilla ◽  
Maria E Fernandez ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mobile Health ◽  
Self Efficacy ◽  
Large Scale ◽  
Cell Disease ◽  
Prescribing Behavior ◽  
Blood Institute ◽  
Mhealth Intervention ◽  
Knowledge Barriers

Background Hydroxyurea prevents disease complications among patients with sickle cell disease (SCD). Although its efficacy has been endorsed by the National Health Lung and Blood Institute evidence-based guidelines, its adoption is low, both by patients with SCD and providers. Mobile health (mHealth) apps provide benefits in improving medication adherence and self-efficacy among patients with chronic diseases and have facilitated prescription among medical providers. However, mHealth has not been systematically tested as a tool to increase hydroxyurea adherence nor has the combination of mHealth been assessed at both patient and provider levels to increase hydroxyurea utilization. Objective This study aims to increase hydroxyurea utilization through a combined two-level mHealth intervention for both patients with SCD and their providers with the goals of increasing adherence to hydroxyurea among patients and improve hydroxyurea prescribing behavior among providers. Methods We will test the efficacy of 2 mHealth interventions to increase both patient and provider utilization and knowledge of hydroxyurea in 8 clinical sites of the NHLBI-funded Sickle Cell Disease Implementation Consortium (SCDIC). The patient mHealth intervention, InCharge Health, includes multiple components that address memory, motivation, and knowledge barriers to hydroxyurea use. The provider mHealth intervention, Hydroxyurea Toolbox (HU Toolbox), addresses the clinical knowledge barriers in prescribing and monitoring hydroxyurea. The primary hypothesis is that among adolescents and adults with SCD, adherence to hydroxyurea, as measured by the proportion of days covered (the ratio of the number of days the patient is covered by the medication to the number of days in the treatment period), will increase by at least 20% after 24 weeks of receiving the InCharge Health app, compared with their adherence at baseline. As secondary objectives, we will (1) examine the change in health-related quality of life, acute disease complications, perceived health literacy, and perceived self-efficacy in taking hydroxyurea among patients who use InCharge Health and (2) examine potential increases in the awareness of hydroxyurea benefits and risks, appropriate prescribing, and perceived self-efficacy to correctly administer hydroxyurea therapy among SCD providers between baseline and 9 months of using the HU Toolbox app. We will measure the reach, adoption, implementation, and maintenance of both the InCharge Health and the HU Toolbox apps using the reach, effectiveness, adoption, implementation, and maintenance framework and qualitatively evaluate the implementation of both mHealth interventions. Results The study is currently enrolling study participants. Recruitment is anticipated to be completed by mid-2021. Conclusions If this two-level intervention, that is, the combined use of InCharge Health and HU Toolbox apps, demonstrates efficacy in increasing adherence to hydroxyurea and prescribing behavior in patients with SCD and their providers, respectively, both apps will be offered to other institutions outside the SCDIC through a future large-scale implementation-effectiveness study. Trial Registration ClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167 International Registered Report Identifier (IRRID) DERR1-10.2196/16319

scholarly journals Alpha-1 Antitrypsin and SERPINA1 gene Mutation As New Biomarker in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4918-4918
Author(s):  
Magda Oliveira Seixas Carvalho ◽  
Carvalho Luís André ◽  
Mauri­cio Batista Carvalho ◽  
Larissa Carneiro Rocha ◽  
Valma Maria Lopes Nascimento ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Gene Polymorphisms ◽  
Clinical History ◽  
Control Group ◽  
Cell Disease ◽  
Serpina1 Gene ◽  
Alpha 1 Antitrypsin

Abstract Sickle cell disease (SCD) has heterogeneous clinical picture and there are several pathway involved in SCD pathogenesis, and chronic inflammation and hemolysis are important hallmarks of the disease. Based on such points, there is a search for prognostic markers to establish possible sub-genotypes of the disease. The present study investigated the alpha-1 antitrypsin (AAT) levels, a serum glycoprotein inhibitor of proteases responsible for trigger inflammatory reactions, describing its associations with SERPINA1 gene polymorphisms, hematological and chemistry biomarkers, and clinical history in a group of SCD children in steady-state. The study was approved at FIOCRUZ research board and followed the principle of Declaration of Helsinki. A total of 356 steady state unrelated SCD patients were included at the present study and a control group (CG) compound by 100 unrelated healthy individuals sex and age matched with the patients group, which were from the same geographical origin. Patients age ranging 13.96+9.91 years of age, the AAT levels higher than the 50th percentile (158.0 mg/mL) had significantly lower red blood cells (RBC) count (p=0.003), hemoglobin (Hb) (p=0.0002) and hematocrit (Hct) (0.0002) concentration, and higher white blood cells (WBC) (p=0.004) and neutrophils (p=0.0001) counts, and higher C-reactive protein (CRP) levels (p<0.0001), and lower urea levels (p=0.0003). AAT had significant negative correlation with RBC (r=-0.205, p=0.0001), Hb (r=-0.203, p=0.0001), Hct (r=-0.256, p<0.0001), high density lipoprotein cholesterol (HDL-C) (r=-0.205, p=0.0001), urea (r=-0.184, p=0.0005), creatinine (r=-134, p=0.012), and albumin (r=-0.135, p=0.011), and significant positive correlation with WBC (r=0.18, 0.0007), neutrophils (r=0.2297, p<0.0001), HbS (r=0.2874), total bilirubin (r=0.137, p=0.01), direct bilirubin (r=0.136, p=0.001), indirect bilirubin (r=0.115, p=0.032), lactate dehydrogenase (r=0.159, p=0.003), ferritin (r=0.1353, 9=0.011), CRP (r=0.355, p<0.0001). Patients with higher levels of AAT had clinical history of more than three infection episodes (OR=1.71, CI:1.05-2.65, p=0.02), gallstones presence (OR=1.75, CI:1.03-2.97, p=0.02), and received more blood therapy (OR=2.35, CI:1.51-3.65, p=0.0001).The SERPINA1 gene polymorphisms were analyzed in 126 SCD patients and 100 CG individuals, the protease inhibitor (Pi)*MM or wide type genotype was find in 115 (91.3%) of SCD patients and 92 (92%) of CG; the PI*SS genotype was find in 2 (1.6%) SCD patients and in none individual of the CG; the PI*MS genotype was find in 9 (7.1%) SCD patients and in 6 (6%) CG individuals; and the PI*MZ genotype was find in 2 (2%) CG individuals. Ours results suggest that the AAT may be considerer as a marker of SCD patients’ outcome, once increased levels is related to stress situation, anti-inflammatory and inhibitory proteases properties and may act as a physiological and cytoprotective regulator influencing the severity of SCD. Our results related to SERPINA1 genotypes emphasize the role of the mutant allele in decrease the AAT production what may represent a risk factor. Additional studies should be carried out in order to investigate mechanisms throughout the AAT can induce several important events in the SCD pathogenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evaluation of Alpha-1 Antitrypsin Levels and SERPINA1 Gene Polymorphisms in Sickle Cell Disease

2017 ◽  
Vol 8 ◽  
Author(s):  
Magda Oliveira Seixas Carvalho ◽  
André Luís Carvalho Santos Souza ◽  
Mauricio Batista Carvalho ◽  
Ana Paula Almeida Souza Pacheco ◽  
Larissa Carneiro Rocha ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Gene Polymorphisms ◽  
Cell Disease ◽  
Serpina1 Gene ◽  
Alpha 1 Antitrypsin

An Elevated Tricuspid Regurgitant Jet Velocity in Sickle Cell Disease Is Associated with Polymorphisms in Genes Impacting Innate Immunity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 514-514
Author(s):  
Harold T. Bae ◽  
Clinton T. Baldwin ◽  
Mark T Gladwin ◽  
Allison E Ashley-Koch ◽  
Melanie Garrett ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Sickle Cell Disease ◽  
Candidate Gene ◽  
Sickle Cell ◽  
P Value ◽  
Cell Disease ◽  
A Genome ◽  
Candidate Gene Studies ◽  
Jet Velocity ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Abstract 514 An elevated tricuspid regurgitant jet velocity (TRV) by echocardiography, associated with increased mortality risk, may be reflective of pulmonary and systemic vasculopathy in sickle cell disease (SCD). The epidemiologic associations between an elevated TRV and other sub-phenotypes of SCD, such as leg ulcers, priapism, proteinuria and increased rate of hemolysis, suggest a common pathogenic link across vascular beds. We were interested in identifying genetic modifiers of SCD and hypothesized that an elevated TRV is, in part, genetically determined. Previous candidate gene studies identified single nucleotide polymorphisms (SNPs) in activin A receptor, type II-like 1 (ACVRL1), bone morphogenetic receptor 2 (BMPR2) and bone morphogenetic protein 6 (BMP6) associated with an elevated TRV suggesting a role for the TGF-b pathway in pathogenesis. We performed a genome-wide association study (GWAS) to identify novel genes and pathways that might be associated with an elevated TRV. We first used Illumina 610K arrays in a GWAS on 340 sickle cell disease patients recruited as part of the observational arm of the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) clinical trial (discovery set) and then validated these results using a replication set consisting of 56 patients enrolled in the studies of TRV and SCD at Duke and Boston Universities. All subjects were 17 years or older and had the HbS only phenotype. We analyzed the data using TRV as a continuous variable and we adjusted for potential confounding effects of age and gender. In addition, as there were 9 different clinical centers in the discovery set, we used center-adjusted TRV values for the analysis. We identified 3 SNPs in CUB and sushi multiple domains 1 (CSMD1) (rs12674750, p=9.5 × 10−6, rs7008391, p=1.8×10−5, rs4433172, p=4.1×10−5) and 1 in sorting nexin 31 (SNX31) (rs1609, p=8.2×10−5), also on chromosome 8q, which were also identified in our replication set (p=0.04 for CSMD1 SNPs and 0.01 for SNX31). CSMD1 is a very large gene of more than 2 Mb and the 610 array includes 1710 SNPs in this gene. However, the probability that we observe 3 SNPs replicated in this gene in a sample size of 56 by chance is only 0.0005. Additionally, 2 SNPs in the mediator of innate immunity, lymphocyte antigen 86 (LY86) (rs3827783, p=3.89×10−6, rs9502483, p=1.02×10−5), were identified in our discovery set. We evaluated the top 5 SNPs originally identified in the candidate gene studies and found that 4 were not present on the 610K arrays. The remaining one had a p-value of 0.17 but is in linkage dysequilibrium with another SNP in BMP6 (rs7450930), a rare variant, with a p-value of 2.5 × 10−5. CSMD1 inhibits the classical pathway of complement activation and complement-mediated hemolysis in rats. This is of interest in SCD because of recent data linking cell-free heme and immune modulation. These findings suggest that sickle cell disease patients with an elevated TRV have altered innate immunity and that sickle vasculopathy may be associated with dysregulation of inflammation. Disclosures: No relevant conflicts of interest to declare.

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