Sophocleous Froso, Archer Natasha M, Lederer Carsten W
Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology & Genetics, 6 Iroon Avenue, Ayios Dometios, Nicosia 2371, Cyprus.
Pediatric Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
Int J Mol Sci. 2025 May 7;26(9):4456. doi: 10.3390/ijms26094456.
Sickle cell disease (SCD) is a group of recessive diseases caused by the β sickling mutation of in homozygosity or in compound heterozygosity with other pathogenic mutations. Patients with severe SCD typically experience painful vaso-occlusive crises and other pain-related phenomena, including acute chest syndrome, priapism, dactylitis, avascular necrosis, and splenic sequestration and infarction. High variability of pain-related phenomena per SCD genotype indicates genetic disease modifiers (GDMs) as pathology determinants and, thus, as critical to prognosis, treatment choice, and therapy development. Articles likely holding genetic information for SCD pain phenomena were identified in PubMed and SCOPUS for article quality assessment and extraction of corresponding GDMs and observations indicative of development areas in our understanding of SCD GDMs. This process led to the initial selection of 183 articles matching the search terms, which, after two-step selection, resulted in the inclusion of 100 articles for content analysis and of significant findings for GDMs from 37 articles. Published data point to gender effects and to 51 GDM SNVs, deletions, and regions, including globin genes and significant overrepresentation of gene ontology pathways related, e.g., to oxidative stress, hypoxia, and regulation of blood pressure. Analyzed articles further pointed to additional candidate GDMs affecting SCD VOC and pain phenomena and to potential confounding factors for GWAS analyses. We found that despite the critical importance of VOC and pain phenomena for SCD pathology, corresponding clinically relevant genetic insights are held back by a shortage of large-scale, systematic multi-ethnic efforts, as undertaken by the INHERENT Network.
镰状细胞病（SCD）是一组隐性疾病，由β链基因突变纯合子或与其他致病基因突变的复合杂合子引起。重度SCD患者通常会经历疼痛性血管闭塞危象和其他与疼痛相关的现象，包括急性胸综合征、阴茎异常勃起、指（趾）炎、无血管性坏死以及脾隔离和梗死。每个SCD基因型的疼痛相关现象高度可变，这表明遗传疾病修饰因子（GDMs）是病理决定因素，因此对预后、治疗选择和治疗发展至关重要。在PubMed和SCOPUS中识别出可能包含SCD疼痛现象遗传信息的文章，以进行文章质量评估，并提取相应的GDMs以及表明我们对SCD GDMs理解中发展领域的观察结果。这一过程导致初步筛选出183篇与搜索词匹配的文章，经过两步筛选后，最终纳入100篇文章进行内容分析，并从37篇文章中得出GDMs的重要发现。已发表的数据指出了性别影响以及51个GDM单核苷酸变异、缺失和区域，包括珠蛋白基因以及与氧化应激、缺氧和血压调节等相关的基因本体途径的显著过度表达。分析的文章还指出了影响SCD VOC和疼痛现象的其他候选GDMs以及全基因组关联研究（GWAS）分析的潜在混杂因素。我们发现，尽管VOC和疼痛现象对SCD病理至关重要，但像INHERENT网络所开展的大规模、系统性多民族研究的缺乏阻碍了相应的临床相关遗传学见解的发展。
