Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Hematology, St Jude Children's Research Hospital, Memphis, Tennessee.
JAMA Netw Open. 2023 Oct 2;6(10):e2337484. doi: 10.1001/jamanetworkopen.2023.37484.
Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.
To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.
PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.
At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.
Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.
Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.
The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.
The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.
镰状细胞病（SCD）是一种单基因疾病，但临床结果受到其他遗传因素的影响。尽管经过了几十年的研究，但 SCD 的遗传学仍未得到很好的理解。
评估所有已报道的 SCD 遗传修饰因子，评估相关研究的设计，并根据现代遗传研究建议为未来的分析提供指导。
通过 2023 年 5 月 16 日对 PubMed、Web of Science 和 Scopus 进行了搜索，确定了 5290 篇出版物。
至少有 2 名评审员确定了 571 篇原创的、经过同行评审的英文出版物，这些出版物报告了人类 SCD 表型的遗传修饰因子，其结果不是治疗反应，且比较不是 SCD 亚型之间的比较，也不包括健康对照。
根据 STREGA 和 PRISMA 指南提取、评估和呈现了与所有 SCD 遗传修饰因子相关的数据。进行了加权 z 分数荟萃分析和途径分析。
结果分为 25 个类别，分为急性并发症、慢性疾病、血液学参数或生物标志物以及 SCD 严重程度的一般或混合指标。
这 571 项纳入的研究报告了来自 43 个国家的 29670 名独特个体（50%≤18 岁）的 17757 项独特结果（4890 项具有统计学意义）。在 1552 个基因中，有 3675 项结果符合荟萃分析的研究标准：报告了表型和基因型、关联大小和方向、变异性测量、样本量和统计检验。只有 62 项关联中的 173 项结果可以进行跨研究合并。其余的关联不能进行汇总，因为它们只报告了一次，或者方法（例如研究设计、报告实践）和基因型或表型定义不够协调。调节胎儿血红蛋白和α-地中海贫血（SCD 严重程度的重要标志物）的基因变异经常被发现：BCL11A、HBS1L-MYB 和 HBG2 中的 19 个单核苷酸变异与胎儿血红蛋白显著相关（绝对值 Z=4.00 至 20.66；P=8.63×10-95 至 6.19×10-5），α-地中海贫血缺失与血红蛋白水平升高和白蛋白尿、异常经颅多普勒速度和中风风险降低显著相关（绝对值 Z=3.43 至 5.16；P=2.42×10-7 至 6.00×10-4）。然而，其他关联仍未得到证实。显著基因的途径分析突出了细胞黏附、炎症、氧化和毒性应激以及血管调节在 SCD 中的重要性（前 25 个基因本体途径中有 23 个涉及这些过程），并提出了未来的研究领域。
这项对所有已发表的 SCD 遗传修饰因子的全面系统评价和荟萃分析的研究结果表明，实施标准化的表型、统计方法和报告实践应加速遗传修饰因子的发现和验证，以及开发临床可操作的遗传特征。
