The Differential Expression of Circulating MicroRNAs in Sickle Cell Trait and Sickle Cell Anemia compared to the Normal Hemoglobin Phenotype.

The heterozygous inheritance of the sickle cell gene, called sickle cell trait (HbAS), was previously thought to be benign. HbAS is now associated with an increased risk for chronic kidney disease, pulmonary embolisms, and exertional rhabdomyolysis. The role of gene expression, as regulated by microRNAs, in these clinical HbAS associations has not been investigated. We explored the association between HbAS and the differential expression of circultaing (plasma) microRNAs when compared to the normal hemoglobin phenotype (HbAA). In stark contrast, the homozygous inheritance of the sickle cell gene, called sickle cell anemia (HbSS) is a severe disease that was previously associated with early mortality and severe morbidity. With appropriate care and early interventions, people with HbSS have improved life expectancy but still experience significant morbidity including cardiac, kidney, and pulmonary disease. The role of gene expression as regulated by microRNA in these clinical HbSS associations has not been investigated. We also explored whether the presence of HbSS is associated with the differential expression of circultaing (plasma) microRNAs as compared to the normal hemoglobin phenotype (HbAA). Overall design: Circulating microRNA profiles in frozen plasma samples obtained from self-identified Black race human subjects with HbAS, HbSS, and HbAA selected from the Mass General Brigham Biobank. HbAA (controls) were matched to HbAS (1:1) and HbSS (1:3) based on age, sex, and eGFR. All subjects were healthy with no comorbidities.

镰状细胞基因的杂合遗传形式即镰状细胞性状（HbAS），此前被认为是良性表型。如今研究发现，镰状细胞性状与慢性肾病、肺栓塞及劳力性横纹肌溶解症的发病风险升高相关。目前尚未有研究探讨微小RNA（microRNAs）调控的基因表达在镰状细胞性状的上述临床关联中所发挥的作用。本研究对比正常血红蛋白表型（HbAA），探讨了镰状细胞性状与循环（血浆）微小RNA差异表达之间的关联。
与之截然不同的是，镰状细胞基因的纯合遗传形式即镰状细胞贫血（HbSS）是一种严重疾病，此前被认为与早期死亡及严重并发症相关。尽管通过恰当的护理与早期干预，镰状细胞贫血患者的预期寿命已得到改善，但他们仍会经历包括心脏、肾脏及肺部疾病在内的显著并发症。目前同样尚未有研究探讨微小RNA调控的基因表达在镰状细胞贫血的上述临床关联中所发挥的作用。本研究还对比正常血红蛋白表型（HbAA），探讨了镰状细胞贫血是否与循环（血浆）微小RNA的差异表达相关。
整体实验设计：本研究从麻省总医院布里格姆生物样本库中选取自我报告为黑人种族的人类受试者，采集其冰冻血浆样本以分析循环微小RNA表达谱。受试者分为HbAS组、HbSS组及HbAA对照组，其中HbAA对照组与HbAS组按1:1比例匹配，与HbSS组按1:3比例匹配，匹配因素包括年龄、性别及估算肾小球滤过率（eGFR）。所有受试者均为健康个体，无合并症。