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 func...
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Frontiers Media S.A.
2020-09-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.02041/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Robert Girot Indou Deme Ly Ana Cristina Silva Pinto Ana Cristina Silva Pinto Vanderson Rocha Francisco Fernandes Ibrahima Diagne Yahia Benzerara Carla L. Dinardo Julia Pavan Soler Simone Kashima Simone Kashima Itauá Leston Araujo Chantal Kenzey Chantal Kenzey Guilherme H. H. Fonseca Evandra S. Rodrigues Evandra S. Rodrigues Fernanda Volt Fernanda Volt Luciana Jarduli Luciana Jarduli Annalisa Ruggeri Annalisa Ruggeri Annalisa Ruggeri Christina Mariaselvam Sandra F. M. Gualandro Hanadi Rafii Hanadi Rafii Barbara Cappelli Barbara Cappelli Felipe Melo Nogueira Graziana Maria Scigliuolo Graziana Maria Scigliuolo Renato Luiz Guerino-Cunha Renato Luiz Guerino-Cunha Kelen Cristina Ribeiro Malmegrim Belinda P. Simões Eliane Gluckman Eliane Gluckman Ryad Tamouza |
spellingShingle |
Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Robert Girot Indou Deme Ly Ana Cristina Silva Pinto Ana Cristina Silva Pinto Vanderson Rocha Francisco Fernandes Ibrahima Diagne Yahia Benzerara Carla L. Dinardo Julia Pavan Soler Simone Kashima Simone Kashima Itauá Leston Araujo Chantal Kenzey Chantal Kenzey Guilherme H. H. Fonseca Evandra S. Rodrigues Evandra S. Rodrigues Fernanda Volt Fernanda Volt Luciana Jarduli Luciana Jarduli Annalisa Ruggeri Annalisa Ruggeri Annalisa Ruggeri Christina Mariaselvam Sandra F. M. Gualandro Hanadi Rafii Hanadi Rafii Barbara Cappelli Barbara Cappelli Felipe Melo Nogueira Graziana Maria Scigliuolo Graziana Maria Scigliuolo Renato Luiz Guerino-Cunha Renato Luiz Guerino-Cunha Kelen Cristina Ribeiro Malmegrim Belinda P. Simões Eliane Gluckman Eliane Gluckman Ryad Tamouza Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease Frontiers in Immunology sickle cell retinopathy sickle cell disease inflammation markers NK cell receptors and ligands toll-like receptor (TLR) non-classical HLA |
author_facet |
Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Karina Tozatto-Maio Robert Girot Indou Deme Ly Ana Cristina Silva Pinto Ana Cristina Silva Pinto Vanderson Rocha Francisco Fernandes Ibrahima Diagne Yahia Benzerara Carla L. Dinardo Julia Pavan Soler Simone Kashima Simone Kashima Itauá Leston Araujo Chantal Kenzey Chantal Kenzey Guilherme H. H. Fonseca Evandra S. Rodrigues Evandra S. Rodrigues Fernanda Volt Fernanda Volt Luciana Jarduli Luciana Jarduli Annalisa Ruggeri Annalisa Ruggeri Annalisa Ruggeri Christina Mariaselvam Sandra F. M. Gualandro Hanadi Rafii Hanadi Rafii Barbara Cappelli Barbara Cappelli Felipe Melo Nogueira Graziana Maria Scigliuolo Graziana Maria Scigliuolo Renato Luiz Guerino-Cunha Renato Luiz Guerino-Cunha Kelen Cristina Ribeiro Malmegrim Belinda P. Simões Eliane Gluckman Eliane Gluckman Ryad Tamouza |
author_sort |
Karina Tozatto-Maio |
title |
Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease |
title_short |
Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease |
title_full |
Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease |
title_fullStr |
Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease |
title_full_unstemmed |
Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease |
title_sort |
polymorphisms in inflammatory genes modulate clinical complications in patients with sickle cell disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-09-01 |
description |
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. |
topic |
sickle cell retinopathy sickle cell disease inflammation markers NK cell receptors and ligands toll-like receptor (TLR) non-classical HLA |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.02041/full |
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doaj-67cb8a7ed9504d0aaebc582eaf5a2b7d2020-11-25T03:28:48ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-09-011110.3389/fimmu.2020.02041553988Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell DiseaseKarina Tozatto-Maio0Karina Tozatto-Maio1Karina Tozatto-Maio2Karina Tozatto-Maio3Robert Girot4Indou Deme Ly5Ana Cristina Silva Pinto6Ana Cristina Silva Pinto7Vanderson Rocha8Francisco Fernandes9Ibrahima Diagne10Yahia Benzerara11Carla L. Dinardo12Julia Pavan Soler13Simone Kashima14Simone Kashima15Itauá Leston Araujo16Chantal Kenzey17Chantal Kenzey18Guilherme H. H. Fonseca19Evandra S. Rodrigues20Evandra S. Rodrigues21Fernanda Volt22Fernanda Volt23Luciana Jarduli24Luciana Jarduli25Annalisa Ruggeri26Annalisa Ruggeri27Annalisa Ruggeri28Christina Mariaselvam29Sandra F. M. Gualandro30Hanadi Rafii31Hanadi Rafii32Barbara Cappelli33Barbara Cappelli34Felipe Melo Nogueira35Graziana Maria Scigliuolo36Graziana Maria Scigliuolo37Renato Luiz Guerino-Cunha38Renato Luiz Guerino-Cunha39Kelen Cristina Ribeiro Malmegrim40Belinda P. Simões41Eliane Gluckman42Eliane Gluckman43Ryad Tamouza44Eurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilCHU Tenon, Paris, FranceNational Children Hospital Center Albert Royer, Cheikh Anta Diop University, Dakar, SenegalFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilCenter for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, BrazilDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilInstituto de Matematica e Estatistica da Universidade de São Paulo, São Paulo, BrazilNational Children Hospital Center Albert Royer, Cheikh Anta Diop University, Dakar, SenegalDépartement de Bactériologie, Hôpital Saint-Antoine, Hôpitaux de l'Est parisien, Paris, FranceDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilInstituto de Matematica e Estatistica da Universidade de São Paulo, São Paulo, BrazilFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilCenter for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil0INSERM 1160, Université Paris 7, Paris, FranceEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilCenter for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, BrazilEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoCenter for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil1School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, BrazilEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, France2Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy3Cellular Therapy and Immunobiology Working Party, The European Society for Blood and Marrow Transplantation, Paris, France4INSERM U955, CHU Henri Mondor, Créteil, FranceDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoDisciplina de Hematologia e Hemoterapia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, MonacoFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilCenter for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil1School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, BrazilFaculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilEurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, FranceMonacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, Monaco4INSERM U955, CHU Henri Mondor, Créteil, FranceSickle 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.02041/fullsickle cell retinopathysickle cell diseaseinflammation markersNK cell receptors and ligandstoll-like receptor (TLR)non-classical HLA |