Vascular occlusions trigger most of the acute and chronic sickle cell anemia (HbSS) clinical complications and have been associated with high levels of soluble adhesion molecules and leukocytes activation. Accumulated evidence from clinical and experimental data shows that endothelin-1 (ET-1) plays an important role in the pathophysiology of the vascular system, because of its vasoconstrictor and hypertrophic activities. Endothelial nitric oxide synthase (eNOS) is an enzyme involved in nitric oxide (NO) synthesis pathway, a potent vasodilator and anti-inflammatory molecule. Polymorphisms in ET-1 and eNOS genes are associated with disturbance in ET-1 production and with reduced NO production respectively. The aim of this study was investigate the ET-1 5665G>T gene polymorphism and eNOS 786T>C gene promoter polymorphism with levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) and soluble Vascular Cell Adhesion Molecule 1 (sVCAM-1), biochemical markers and medical history of HbSS patients.
We studied 51 HbSS patients from Northeast Brazil in attendance of the outpatient's clinic of the Foundation of Hematology and Hemotherapy of Bahia (HEMOBA). Biochemical analyses were measured by colorimetric methods, soluble adhesion molecules were measured by ELISA and the complete medical history was recorded by patient's record. The study was approved by the FIOCRUZ ethical committee and informed consents were signed by patients or official responsible.cerqueira
Our results showed genotype frequencies of 62.7% (32/51) of wild type (GG), 35.3% (18/51) of heterozygous (GT) and 2% (1/51) of homozygous (TT) for ET-1 5665G>T gene polymorphism. The eNOS 786T>C gene polymorphism showed 60.5% (23/38) of wild type, 34.2% (13/38) of heterozygous and 5.3% (2/38) homozygous. Both polymorphisms were in Hardy-Weinberg equilibrium. HbSS patients carriers of eNOS mutant allele (C) had the highest levels of sVCAM-1 (p= 0.015) (Fig. 1). Levels of sICAM were not related to any studied gene polymorphism. However, regarding to patients clinical history, we found a raised occurrence of acute chest syndrome (ACS) in carries of the ET-1 5665G>T mutant allele (Fig. 2).
Our study suggests that eNOS 786T>C and ET-1 5665G>T gene polymorphisms can participate of the HbSS pathophysiology. It is well known that high levels of circulating sVCAM are associating to an increased inflammatory state and VOC susceptibility, and our data show that eNOS variant in HbSS patients might be important to NO activity and anti-inflammatory vascular process. Also, the raised frequency of ACS, a major clinical feature in SCA which leads to patient mortality, was associated with the ET-1 variant showing the importance of the studied genes screening and their participation in these key molecules mechanism related to vascular health and VOC process.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.