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

ABSTRACT: 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.

SUBMITTER: Tozatto-Maio K

PROVIDER: S-EPMC7510050 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Tozatto-Maio Karina K Girot Robert R Ly Indou Deme ID Silva Pinto Ana Cristina AC Rocha Vanderson V Fernandes Francisco F Diagne Ibrahima I Benzerara Yahia Y Dinardo Carla L CL Soler Julia Pavan JP Kashima Simone S Araujo Itauá Leston IL Kenzey Chantal C Fonseca Guilherme H H GHH Rodrigues Evandra S ES Volt Fernanda F Jarduli Luciana L Ruggeri Annalisa A Mariaselvam Christina C Gualandro Sandra F M SFM Rafii Hanadi H Cappelli Barbara B Nogueira Felipe Melo FM Scigliuolo Graziana Maria GM Guerino-Cunha Renato Luiz RL Malmegrim Kelen Cristina Ribeiro KCR Simões Belinda P BP Gluckman Eliane E Tamouza Ryad R

Frontiers in immunology 20200904

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 ...[more]

PMID: 33013863

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Project description:ObjectivesThis study evaluated the prevalence rate of vaso-occlusive crisis (VOC) episodes, rates of uncomplicated and complicated VOC episodes, and the primary reasons for emergency room (ER) visits and inpatient admissions for sickle cell disease (SCD) patients.MethodsThe Medicaid Analytic extracts database was used to identify adult SCD patients using claims from 01JUL2009-31DEC2012. The date of the first observed SCD claim was designated as the index date. Patients were required to have continuous medical and pharmacy benefits for ≥6 months baseline and ≥12 months follow-up period. Patient demographics, baseline clinical characteristics, the rate of uncomplicated and complicated VOC (VOC with concomitant SCD complications) episodes, and reasons for ER visits and inpatient stays were analyzed descriptively.ResultsA total of 8,521 patients were included in the analysis, with a median age of 30 years. The average follow-up period was 2.7 years. The rate of VOC episodes anytime in the follow-up was 3.31 in person-years. During the first-year follow-up period, an average of 2.79 VOC episodes were identified per SCD patients, with 1.06 VOC episodes treated in inpatient setting and 0.90 VOC episodes in ER without admission. A total of 76,154 VOC episodes were identified during the entire follow-up period for the overall SCD patients. Most of the VOC episodes (70.3% [n = 53,523]) were uncomplicated episodes, and 29.7% were complicated episodes. Using primary diagnosis claims only, the most frequent complications during the VOC episode were infectious diseases (25.9%), fever (21.8%), and pulmonary disorders (16.2%). Among ER and hospitalizations related to VOC or SCD complication, ~85.0% had VOCs as the primary reason for admission; 15.0% had SCD complications as the primary reason.ConclusionIn summary, SCD and its related comorbidities and complications result in high acute health care utilization. In addition, VOC remains the primary reason for SCD patients' ER visits and inpatient admissions.

Dataset Information

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

Publications

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

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