TY - JOUR
T1 - Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease
AU - Tozatto-Maio, Karina
AU - Girot, Robert
AU - Ly, Indou Deme
AU - Silva Pinto, Ana Cristina
AU - Rocha, Vanderson
AU - Fernandes, Francisco
AU - Diagne, Ibrahima
AU - Benzerara, Yahia
AU - Dinardo, Carla L.
AU - Soler, Julia Pavan
AU - Kashima, Simone
AU - Araujo, Itauá Leston
AU - Kenzey, Chantal
AU - Fonseca, Guilherme H.H.
AU - Rodrigues, Evandra S.
AU - Volt, Fernanda
AU - Jarduli, Luciana
AU - Ruggeri, Annalisa
AU - Mariaselvam, Christina
AU - Gualandro, Sandra F.M.
AU - Rafii, Hanadi
AU - Cappelli, Barbara
AU - Nogueira, Felipe Melo
AU - Scigliuolo, Graziana Maria
AU - Guerino-Cunha, Renato Luiz
AU - Malmegrim, Kelen Cristina Ribeiro
AU - Simões, Belinda P.
AU - Gluckman, Eliane
AU - Tamouza, Ryad
N1 - Funding Information:
The authors thank the Centre Scientifique de Monaco, CAPES, CTC, all patients, and their families. Funding. This work was supported by the Centre Scientifique de Monaco, by the Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES, grant number 88881.133635/2016-01), and by the Center for Cell-based Therapy (CTC).
Publisher Copyright:
© Copyright © 2020 Tozatto-Maio, Girot, Ly, Silva Pinto, Rocha, Fernandes, Diagne, Benzerara, Dinardo, Soler, Kashima, Araujo, Kenzey, Fonseca, Rodrigues, Volt, Jarduli, Ruggeri, Mariaselvam, Gualandro, Rafii, Cappelli, Nogueira, Scigliuolo, Guerino-Cunha, Malmegrim, Simões, Gluckman and Tamouza.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/4
Y1 - 2020/9/4
N2 - 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.
AB - 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.
KW - CTLA 4
KW - inflammation markers
KW - NK cell receptors and ligands
KW - non-classical HLA
KW - sickle cell complications
KW - sickle cell disease
KW - sickle cell retinopathy
KW - toll-like receptor (TLR)
UR - http://www.scopus.com/inward/record.url?scp=85091524052&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091524052&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.02041
DO - 10.3389/fimmu.2020.02041
M3 - Article
C2 - 33013863
AN - SCOPUS:85091524052
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2041
ER -