Eurocord, Université de Paris, IRSL, Hopital Saint Louis, Paris, France.
Monacord, International Observatory on Sickle Cell Disease, Centre Scientifique de Monaco, Monaco, Monaco.
Front Immunol. 2020 Sep 4;11:2041. doi: 10.3389/fimmu.2020.02041. eCollection 2020.
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 4696480 3804099 , and HLA-G, 9380142 genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G 9380142 allele increased the risk of cholelithiasis ( vs. , OR 1.57, 95%CI 1.16-2.15; vs. , OR 2.47, 95%CI 1.34-4.64; = 0.02). For SNPs located in the loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, 2246809 ( vs. : OR 0.22, 95%CI 0.09-0.50; vs. : OR 0.47, 95%CI 0.31-0.71; = 0.004, for patients of same origin), 2617160 ( vs. : OR 0.67, 95%CI 0.48-0.92; vs. : OR 0.45, 95%CI 0.23-0.84; = 0.04), and 2617169 ( vs. : OR 0.33, 95%CI 0.13-0.82; vs. : OR 0.58, 95%CI 0.36-0.91, = 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.
镰状细胞病（SCD）是全球最常见的单基因疾病，其表型变异性很大，但迄今为止，这一现象仅部分得到了解释。由于炎症在 SCD 病理生理学中起着重要作用，我们假设编码功能重要的炎症蛋白的基因中的单核苷酸多态性（SNP）可能调节 SCD 并发症的发生。我们评估了 20 个 SNP 在编码 Toll 样受体（TLR）、自然杀伤细胞受体（NKG）、组织相容性白细胞抗原（HLA）、主要组织相容性复合体 I 多肽相关序列 A（MICA）和细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的基因之间的关联，以及 6 种 SCD 临床并发症（中风、急性胸部综合征（ACS）、腿部溃疡、胆石症、骨坏死或视网膜病变）的发生情况。这项研究是在 500 名患者的队列中进行的。我们发现，在并发症较少的患者中，4696480 3804099 和 HLA-G 9380142 基因型更为常见。此外，在逻辑回归中，HLA-G 9380142 等位基因增加了胆石症的风险（与相比，OR 1.57，95%CI 1.16-2.15；与相比，OR 2.47，95%CI 1.34-4.64；= 0.02）。对于位于 位点的 SNP，在逻辑回归中，三个 SNP 的 A 等位基因与较低的视网膜病变频率相关，即 2246809（与相比：OR 0.22，95%CI 0.09-0.50；与相比：OR 0.47，95%CI 0.31-0.71；= 0.004，对于同起源的患者），2617160（与相比：OR 0.67，95%CI 0.48-0.92；与相比：OR 0.45，95%CI 0.23-0.84；= 0.04），和 2617169（与相比：OR 0.33，95%CI 0.13-0.82；与相比：OR 0.58，95%CI 0.36-0.91，= 0.049，对于同 SCD 基因型的患者）。这些结果通过揭示对 SCD 并发症的易感性或保护作用，可能有助于更好地理解 SCD 表现中涉及的炎症途径，并为发现预测疾病严重程度的生物标志物铺平道路，从而改善 SCD 的管理。
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