Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Av. Padre Cruz, 1649-016, Lisbon, Portugal.
Centro de Estudos de Ciência Animal, Instituto de Ciências e Tecnologias Agrárias e Agro-Alimentares, Universidade do Porto, Porto, Portugal.
Immunogenetics. 2018 Jan;70(1):37-51. doi: 10.1007/s00251-017-1013-7. Epub 2017 Jun 30.
Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480, and a (GT)n short tandem repeat. The infectious subphenotypes included (A) recurrent respiratory infections and (B) severe bacterial infection at least once during the patient's follow-up. The absence of the haplotype [Del]-T-[n ≥ 17] (Hap7) in homozygocity protected against subphenotype (B), in a statistically significant association, resisting correction for multiple testing. For the individual loci, the same association tendencies were observed as in the haplotype, including a deleterious association between the SNP rs4696480 T allele and subphenotype (A), whereas the A/A genotype was protective, and a deleterious effect of the A/T genotype with subphenotype (B), as well as including the protective effect of -196 to -174 insert (Ins) and deleterious effect of the deletion (Del) in homozygocity, against subphenotype (B). Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyurea treatment), and 3.7-kb alpha-thalassemia. Interestingly, differences between the effects of the two latter covariables favoring a reduction in the incidence rate of subphenotype (B) contrast with a resulting increase in relation to subphenotype (A). These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients.
镰状细胞贫血症（SCA）的特征是慢性溶血、严重血管阻塞危象（VOC）和反复发生的严重感染。一个 95 例 SCA 儿科患者队列是对患者感染性疾病表型和 TLR2 基因三个非编码多态性区域的基因型-表型关联的背景，这三个区域包括 -196 到 -174 缺失插入、SNP rs4696480 和（GT）n 短串联重复。感染亚表型包括（A）复发性呼吸道感染和（B）在患者随访期间至少发生一次严重细菌感染。在纯合状态下缺乏单体型 [Del]-T-[n≥17]（Hap7）可显著保护患者免受亚表型（B）的影响，这种关联在统计学上显著，且不受多重检测校正的影响。对于个别基因座，观察到与单体型相同的关联趋势，包括 SNP rs4696480 T 等位基因与亚表型（A）之间的有害关联，而 A/A 基因型是保护性的，A/T 基因型与亚表型（B）之间的有害关联，以及 -196 到 -174 插入（Ins）的保护性效应和纯合状态下缺失（Del）的有害效应，均针对亚表型（B）。此外，严重细菌感染发生率的降低与溶血评分、胎儿血红蛋白水平（羟基脲治疗前）和 3.7-kb α-地中海贫血的升高相关。有趣的是，这两个后者协变量的影响之间的差异有利于降低亚表型（B）的发生率，而与亚表型（A）的发生率增加形成对比。这些结果可能对降低 SCA 患者发病率和死亡率的医疗保健策略具有实际意义。
