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

Tozatto-Maio, Karina; Girot, Robert; Ly, Ibrahima; Pinto, Ana Cristina Silva; Rocha, Vanderson; Fernandes, Francisco; Diagne, Ibrahima; Benzerara, Yahia; Dinardo, Carla Luana; Soler, Júlia P.; Kashima, Simone; Araujo, Itauá Leston; Kenzey, Chantal; Fonseca, Guilherme Henrique Hencklain; Rodrigues, Evandra Strazza; Volt, Fernanda; Jarduli, Luciana Ribeiro; Ruggeri, Annalisa; Mariaselvam, Christina Mary; Gualandro, Sandra; Rafii, Hanadi; Cappelli, Barbara; Nogueira, Felipe Melo; Scigliuolo, Graziana Maria; Cunha, Renato; Malmegrim, Kelen Cristina Ribeiro; Simões, Belinda Pinto; Gluckman, Éliane; Tamouza, Ryad

doi:10.3389/fimmu.2020.02041

Cited by 12 publications

(11 citation statements)

References 56 publications

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“…However, it is not clear whether there is a significant predisposition to viral infections. On the contrary, there is an increase in the cytotoxic function of NK cells and the activation of naive cytotoxic T lymphocytes that secrete interferon-γ (IFN-γ) [20]. On the other hand, tissue and organ damage deteriorate the natural barrier against infectious agents.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals

et al. 2021

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It is highly expected that COVID-19 infection will have devastating consequences in sickle cell disease (SCD) patients due to endothelial activation and decreased tissue and organ reserve as a result of microvascular ischemia and continuous inflammation. In this study, we aimed to compare the clinical course of COVID-19 in adult SCD patients under the organ injury mitigation and clinical care improvement program (BASCARE) with healthcare professionals without significant comorbid conditions. The study was planned as a retrospective, multicenter and cross-sectional study. Thirty-nine SCD patients, ages 18 to 64 years, and 121 healthcare professionals, ages 21 to 53, were included in the study. The data were collected from the Electronic Health Recording System of PRANA, where SCD patients under the BASCARE program had been registered. The data of other patients were collected from the Electronic Hospital Data Recording System and patient files. In the SCD group, the crude incidence of COVID-19 was 9%, while in healthcare professionals at the same period was 23%. Among the symptoms, besides fever, loss of smell and taste were more prominent in the SCD group than in healthcare professionals. There was a significant difference between the two groups in terms of development of pneumonia, hospitalization, and need for intubation (43 vs 5%, P < 0.00001; 26 vs 7%, P = 0.002; and 10 vs 1%, P = 0.002, respectively). Prophylactic low molecular weight heparin and salicylate were used more in the SCD group than in healthcare professionals group (41 vs 9% and 28 vs 1%; P < 0.0001 for both). The 3-month mortality rate was demonstrated as 5% in the SCD group, while 0 in the healthcare professionals group. One patient in the SCD group became continously dependent on respiratory support. The cause of death was acute chest syndrome in the first case, hepatic necrosis and multi-organ failure in the second case. In conclusion, these observations supported the expectation that the course of COVID-19 in SCD patients will get worse. The BASCARE program applied in SCD patients could not change the poor outcome.

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Section: Discussionmentioning

confidence: 99%

Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals

et al. 2021

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“…T allele frequency higher in South Indian rheumatoid arthritis patients with deformities-marker of severe disease [80] A allele associated with lower frequency of retinopathy-vascular complication in sickle cell disease in Sub-Saharan African and French West Indian patients [79] rs2617170 (T > C) KLRC4 exon 3 TT homozygosity associated with lower risk of recurrent miscarriage among North African women [81] rs7397310 (T > C) 3' flanking region of KLRK1 No association between alleles frequency and cholangiocarcinoma risk in Caucasian individuals [82] rs2900420 (G > A) 3' flanking region of KLRK1 A allele associated with better survival time in advanced-stage non-small cell lung cancer Non-Hispanic Whites patients treated with first-line chemotherapy [83] rs10772271 (G > A) 3' flanking region of KLRK1 A allele associated with decreased NKG2D expression on NK cells in Finnish infants, and increased viral bronchiolitis susceptibility [84] rs11053781 (G > A) KLRK1 intron 3 Higher G allele frequency in PSC Scandinavian patients with cholangiocarcinoma [85] rs7972757 (A > G) Intergenic KLRC4-KLRK1 Higher A allele frequency in placental malaria affected African patients [86] rs728010 (G > A) Intergenic KLRC4-KLRK1 Higher GG genotype frequency in placental malaria affected African patients [86] rs12821887 (T > C) Intergenic KLRC4-KLRK1 Higher TT genotype frequency in placental malaria affected African patients [86] rs2617167 (G > A) Intergenic KLRC4-KLRK1 Higher A allele frequency in PSC Scandinavian patients with cholangiocarcinoma [85] Table 2. Cont.…”

Section: Gg Genotype Associated With Inefficient Anti-tnf Therapy In Rheumatoid Arthritismentioning

confidence: 99%

“…Caucasian patients [64] TT genotype in Taiwanese chronic hepatitis B patients associated with a decreased risk of delayed spontaneous HBeAg seroconversion [75] Higher A allele frequency in Japanese congenital CMV infection cases symptomatic at birth than in asymptomatic cases [76] AA and GA genotypes associated with reduced HPV-related cancer risk; protective effect of A allele against the progression to advanced stages of cancer [77] rs2617160 (A > T) Intergenic KLRC4-KLRK1 TT genotype associated with increased risk of chronic hepatitis B in Chinese patients [78] A allele associated with lower frequency of retinopathy-vascular complication in sickle cell disease in Sub-Saharan African and French West Indian patients [79] rs2246809 (A > G) Intergenic KLRC4-KLRK1…”

Section: Gg Genotype Associated With Inefficient Anti-tnf Therapy In Rheumatoid Arthritismentioning

confidence: 99%

“…A allele frequency higher in South Indian rheumatoid arthritis patients with deformities-marker of severe disease [80] A allele associated with lower frequency of retinopathy-vascular complication in sickle cell disease in Sub-Saharan African and French West Indian patients [79] rs2617169 (A > T) KLRC4 intron 3…”

Section: Gg Genotype Associated With Inefficient Anti-tnf Therapy In Rheumatoid Arthritismentioning

confidence: 99%

“…In the next paragraphs, its role in cancer immunosurveillance, autoimmune diseases, transplantation, infections together with the defense mechanisms of target cells to avoid the cytotoxic effect of NK cells as well as NKG2D-based treatment options will be presented and discussed. markers of severe clinical presentation of the disease [65,79,80]. KLRK1 gene polymorphism may represent a potential biomarker for prediction of treatment outcome in patients with cancers, autoimmune diseases or virus induced diseases [62,64,68,70,83].…”

Section: Multiple Functions Of the Activating Nkg2d Receptor-clinical Implications And Application For Treatmentmentioning

confidence: 99%

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NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Siemaszko

Marzec-Przyszlak

Bogunia‐Kubik

2021

Cells

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Natural Killer (NK) cells are natural cytotoxic, effector cells of the innate immune system. They can recognize transformed or infected cells. NK cells are armed with a set of activating and inhibitory receptors which are able to bind to their ligands on target cells. The right balance between expression and activation of those receptors is fundamental for the proper functionality of NK cells. One of the best known activating receptors is NKG2D, a member of the CD94/NKG2 family. Due to a specific NKG2D binding with its eight different ligands, which are overexpressed in transformed, infected and stressed cells, NK cells are able to recognize and attack their targets. The NKG2D receptor has an enormous significance in various, autoimmune diseases, viral and bacterial infections as well as for transplantation outcomes and complications. This review focuses on the NKG2D receptor, the mechanism of its action, clinical relevance of its gene polymorphisms and a potential application in various clinical settings.

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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

Cited by 12 publications

References 56 publications

Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals

Comparison of the clinical course of COVID-19 infection in sickle cell disease patients with healthcare professionals

NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

Genetic Variation and Sickle Cell Disease Severity

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