ABSTRACT
Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia -3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia -3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.
Subject(s)
Anemia, Sickle Cell/complications , alpha-Thalassemia/complications , beta-Globins/genetics , Adolescent , Adult , Aged , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/genetics , Arterial Occlusive Diseases/epidemiology , Arterial Occlusive Diseases/etiology , Brazil/epidemiology , Child , Cholelithiasis/epidemiology , Cholelithiasis/etiology , Female , Fetal Hemoglobin/analysis , Follow-Up Studies , Haplotypes/genetics , Hemolysis , Humans , Leg Ulcer/epidemiology , Leg Ulcer/etiology , Male , Mutation , Stroke/epidemiology , Stroke/etiology , Treatment Outcome , Young Adult , alpha-Thalassemia/blood , alpha-Thalassemia/geneticsSubject(s)
Anemia, Sickle Cell/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Leg Ulcer/genetics , S100 Proteins/genetics , Adult , Brazil , Case-Control Studies , Cohort Studies , Female , Filaggrin Proteins , Genotype , Humans , Inflammation/genetics , Male , Middle Aged , Exome Sequencing/methodsABSTRACT
Leg ulcers (LUs) are a debilitating complication of sickle cell anemia (SCA), with inflammation known to play a crucial role in their pathogenesis. Many studies have described the roles of T helper type 1 (Th1) and Th2 pathways in SCA; however, defects in anti-inflammatory responses are poorly understood. We evaluated interleukin (IL)-10 levels in serum and peripheral blood mononuclear cells (PBMCs) in SCA patients with leg ulcers (SCALU) and without leg ulcers (SCAWH) in addition to CD4(+) CD25(+)FoxP3(+) T cell populations and their its IL-10 expression. In stimulated and unstimulated PBMC cultures, SCALU patients produced higher levels of IL-10 than those in the SCAWH group. Higher levels of IL-10 in SCALU patients correlated with a history of osteonecrosis in stimulated and unstimulated cultures when compared with those in SCAWH. Immunophenotyping revealed that SCALU patients had a higher proportion of CD4(+)CD25(+)FoxP3(+), Tr1 and CD4(+)CD25(+)FoxP3(+)IL-10(+) T cells than other groups. Our findings revealed that IL-10 levels were increased in unstimulated cells from the SCALU group, and that this group also presented with a predominant CD4(+) CD25(+)FoxP3(+) cell population despite many of those cells being IL-10 negative.
