Wonkam Ambroise, Chimusa Emile R, Mnika Khuthala, Pule Gift Dineo, Ngo Bitoungui Valentina Josiane, Mulder Nicola, Shriner Daniel, Rotimi Charles N, Adeyemo Adebowale
Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Clin Transl Med. 2020 Aug;10(4):e152. doi: 10.1002/ctm2.152.
Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA.
Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups.
In the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways.
This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.
镰状细胞贫血（SCA）是一种临床异质性单基因疾病。由于多种因素，包括患者就医便利性、资源获取困难以及缺乏针对SCA的特定有效干预措施，医疗护理对非洲SCA患者临床结局的影响并不理想。
在此背景下，我们对192名接受全外显子测序的非洲参与者进行了研究。参与者包括105名SCA患者，其临床表现各异：一个“长期存活者”组（年龄超过40岁）、一个“中风”组（至少有一次明显的中风发作）和一个“随机”组（年龄小于40岁且无明显脑血管疾病的患者）。还研究了58名种族匹配的纯合血红蛋白A对照者。研究结果在另外独立招募的29名SCA患者样本中得到验证。针对每个组，估计每个基因有害和功能丧失变异的突变负担相对于零模型的统计显著性，并进行基因集关联测试以检验组间差异。
在“长期存活者”组中，有害/功能丧失变异在包括CLCN6（一种电压依赖性氯通道，罕见的有害变异与较低血压有关）和OGHDL（在精氨酸代谢中起重要作用，而精氨酸代谢是SCA的治疗靶点）的基因中富集。在“中风”组中，涉及的重要基因与凝血级联活性增加和补体激活增加有关，例如编码抗凝血酶的SERPINC1。氧化应激和谷氨酸生物合成途径在“长期存活者”组中富集。已发表的转录组学证据为所确定途径的作用提供了功能支持。
本研究提供了有助于SCA临床表型变异的新基因集。所确定的基因和途径为其他干预措施指明了新途径。
