David, SusanaAguiar, PedroAntunes, LilianaDias, AlexandraMorais, AnabelaSakuntabhai, AnavajLavinha, João2017-08-022018-06-302017-06-30Immunogenetics. 2018 Jan;70(1):37-51. doi: 10.1007/s00251-017-1013-7. Epub 2017 Jun 30.1432-1211ESSN: 0093-7711http://hdl.handle.net/10400.18/4785Sickle 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 patientsengAgentes Microbianos e AmbienteDeterminantes Imunológicos em Doenças CrónicasDeterminantes da Saúde e da DoençaDoenças GenéticasEpidemiologia ClínicaInfecções RespiratóriasPatologias do Glóbulo VermelhoSickle CellanemiaTLR2Genetic VariantsViral and Bacterial InfectionHemolytic ComponentGenotype-to-phenotype Associationjournal article10.1007/s00251-017-1013-7