AUTHOR=Tozatto-Maio Karina , Girot Robert , Ly Indou Deme , Silva Pinto Ana Cristina , Rocha Vanderson , Fernandes Francisco , Diagne Ibrahima , Benzerara Yahia , Dinardo Carla L. , Soler Julia Pavan , Kashima Simone , Araujo Itauá Leston , Kenzey Chantal , Fonseca Guilherme H. H. , Rodrigues Evandra S. , Volt Fernanda , Jarduli Luciana , Ruggeri Annalisa , Mariaselvam Christina , Gualandro Sandra F. M. , Rafii Hanadi , Cappelli Barbara , Nogueira Felipe Melo , Scigliuolo Graziana Maria , Guerino-Cunha Renato Luiz , Malmegrim Kelen Cristina Ribeiro , Simões Belinda P. , Gluckman Eliane , Tamouza Ryad 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02041

DOI=10.3389/fimmu.2020.02041

ISSN=1664-3224

ABSTRACT=<p>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 <italic>TLR2 rs</italic>4696480 <italic>TA, TLR2 rs</italic>3804099 <italic>CC</italic>, and HLA-G, <italic>rs</italic>9380142 <italic>AA</italic> genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G <italic>rs</italic>9380142 <italic>G</italic> allele increased the risk of cholelithiasis (<italic>AG</italic> vs. <italic>AA</italic>, OR 1.57, 95%CI 1.16–2.15; <italic>GG</italic> vs. <italic>AA</italic>, OR 2.47, 95%CI 1.34–4.64; <italic>P</italic> = 0.02). For SNPs located in the <italic>NKG2D</italic> loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, <italic>rs</italic>2246809 (<italic>AA</italic> vs. <italic>GG</italic>: OR 0.22, 95%CI 0.09–0.50; <italic>AG</italic> vs. <italic>GG</italic>: OR 0.47, 95%CI 0.31–0.71; <italic>P</italic> = 0.004, for patients of same origin), <italic>rs</italic>2617160 (<italic>AT</italic> vs. <italic>TT</italic>: OR 0.67, 95%CI 0.48–0.92; <italic>AA</italic> vs. <italic>TT</italic>: OR 0.45, 95%CI 0.23–0.84; <italic>P</italic> = 0.04), and <italic>rs</italic>2617169 (<italic>AA</italic> vs. <italic>TT</italic>: OR 0.33, 95%CI 0.13–0.82; <italic>AT</italic> vs. <italic>TT</italic>: OR 0.58, 95%CI 0.36–0.91, <italic>P</italic> = 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.</p>