Saraf Santosh L, Akingbola Titilola S, Shah Binal N, Ezekekwu Chinedu A, Sonubi Omowunmi, Zhang Xu, Hsu Lewis L, Gladwin Mark T, Machado Roberto F, Cooper Richard S, Gordeuk Victor R, Tayo Bamidele O
Division of Hematology & Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL USA.
Department of Hematology, University College Hospital, Ibadan, Nigeria.
Blood Adv. 2017 Apr 25;1(11):693-698. doi: 10.1182/bloodadvances.2017005231.
Alpha-thalassemia and the rs1427407 T allele are commonly observed in sickle cell anemia (SCA) patients and are associated with reduced hemolysis and higher hemoglobin F levels, respectively. We investigated whether a high-risk genetic profile, defined as SCA patients who did not inherit either α-thalassemia or the rs1427407 T allele, had stronger associations with clinical and laboratory variables than the individual genetic components in the University of Ibadan cohort (n=249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC)(n=260) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST)(n=387). High-risk was associated with higher reticulocytes (15.0% vs. 7.8%, =0.08) and stroke history (6% vs. 1%, =0.02) than standard risk patients and these associations were more significant than the individual genetic components in the University of Ibadan cohort. These findings were replicated in high-risk patients from UIC and Walk-PHaSST for reticulocytes (UIC: 13.5% vs. 11.8%, =0.03; Walk-PHaSST: 9.6% vs. 8.2%, =0.0003) and stroke history (UIC: 32% vs. 22%, =0.07; Walk-PHaSST: 14% vs. 7%, =0.01). On combined analysis, high-risk had strong associations with increased markers of hemolysis (hemoglobin β= -0.29, 95%CI: -0.50 to -0.09; =0.006; reticulocyte% β=2.29, 95%CI: 1.31 to 3.25; =1x10) and stroke history (OR=2.0, 95%CI: 1.3 to 3.0; =0.0002), but no association with frequent vaso-occlusive crises (≥3/year). A high-risk genetic profile is associated with increased hemolysis and stroke history in three independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke.
α地中海贫血和rs1427407 T等位基因在镰状细胞贫血（SCA）患者中普遍存在，分别与溶血减少和较高的胎儿血红蛋白水平相关。我们调查了一种高风险基因谱（定义为未遗传α地中海贫血或rs1427407 T等位基因的SCA患者）是否比伊巴丹大学队列（n = 249）中的个体遗传成分与临床和实验室变量有更强的关联。然后我们在芝加哥伊利诺伊大学（UIC）（n = 260）和西地那非治疗肺动脉高压和镰状细胞病（Walk-PHaSST）（n = 387）的SCA队列中重复了我们的研究结果。与标准风险患者相比，高风险与更高的网织红细胞计数（15.0%对7.8%，P = 0.08）和中风病史（6%对1%，P = 0.02）相关，并且这些关联在伊巴丹大学队列中比个体遗传成分更显著。这些发现在UIC和Walk-PHaSST的高风险患者中对于网织红细胞计数（UIC：13.5%对11.8%，P = 0.03；Walk-PHaSST：9.6%对8.2%，P = 0.0003）和中风病史（UIC：32%对22%，P = 0.07；Walk-PHaSST：14%对7%，P = 0.01）得到了重复。综合分析显示，高风险与溶血标志物增加（血红蛋白β = -0.29，95%CI：-0.50至-0.09；P = 0.006；网织红细胞百分比β = 2.29，95%CI：1.31至3.25；P = 1×10⁻⁴）和中风病史（OR = 2.0，95%CI：1.3至3.0；P = 0.0002）有很强的关联，但与频繁的血管闭塞性危机（≥3次/年）无关。一种高风险基因谱与三个独立队列中的溶血增加和中风病史相关。这种基因谱可能有助于识别应优先使用羟基脲治疗以及需要更密切监测中风的患者。
