ABSTRACT
BACKGROUND: The genetic variants of the receptor for advanced glycation end products (RAGE) gene have been associated with vascular disease risk. The objective of this work was to explore the association of three single-nucleotide polymorphisms (SNPs) of RAGE gene (374T/A, 429T/C, and G82S) with vascular complications in SCD. METHODS: The study was conducted on 40 children with SCD and 40 healthy children served as controls. All participants were genotyped for the three studied RAGE polymorphisms by polymerase chain reaction (PCR). RESULTS: Regarding 374T/A polymorphism, the frequency of TA, TT genotypes and T allele were higher in patients (p < 0.001). T allele was associated with higher incidence of sickling crisis and stroke (p < 0.05). In the subgroup analyses of 429T/C polymorphism, an association between C allele and SCD vascular complications was observed (p < 0.05). Concerning the frequency of G82S genotypes of RAGE, GG variant was detected in 39 (97.5%) of the patients, as compared with 40 (100%) of controls (p = 0.3). A regression analysis proved that HbS%, serum ferritin, and the -374T and 429C alleles were significant independent predictors of frequent sickling episodes (p < 0.05). CONCLUSIONS: The C allele of -429T/C and T allele of 374T/A RAGE polymorphisms may be considered as predictors for vascular dysfunction in SCD. IMPACT: The C allele of -429T/C and T allele of 374T/A RAGE polymorphisms may be considered as predictors for vascular dysfunction in SCD patients. To our knowledge, our study is the first exploring the association of three single-nucleotide polymorphisms of RAGE gene (374T/A, 429T/C, and G82S) with vascular complications in SCD. Early identification of patients carrying these genetic variants might be of great importance not only to identify subjects at risk of vasculopathy but also to direct them to RAGE-targeted treatments.
Subject(s)
Anemia, Sickle Cell/genetics , Polymorphism, Single Nucleotide , Receptor for Advanced Glycation End Products/genetics , Vascular Diseases/genetics , Adolescent , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/diagnosis , Case-Control Studies , Child , Cross-Sectional Studies , Egypt , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Phenotype , Prognosis , Risk Assessment , Risk Factors , Stroke/diagnosis , Stroke/genetics , Vascular Diseases/diagnosisABSTRACT
BACKGROUND: Soluble forms of RAGE (sRAGE) have been found circulating in plasma and tissues. Evidence is accruing in human subjects linking levels of sRAGE to oxidative stress in many disorders. Because sickle cell disease (SCD) is a state of oxidative stress, we tested the hypothesis that circulating sRAGE levels may be involved in the vascular pathology of SCD. OBJECTIVES: To determine the sRAGE levels in children and adolescents with SCD and investigate their association with markers of hemolysis, iron overload, and SCD-related organ complications. SUBJECTS AND METHODS: The level of sRAGE was measured in 40 children and adolescent with SCD compared with 40 healthy controls using enzyme-linked immunosorbent assay (ELISA). RESULTS: sRAGE was significantly higher in patients compared with controls (p < 0.001) and was elevated in patients with history of stroke, acute lung syndrome, and frequency of sickling crisis or serum ferritin > 2500 (p < 0.05). Patients with high sRAGE levels are candidates for chelation. sRAGE was positively correlated with HbS% (r = 0.422, p = 0.007), LDH (r = 0.329, p = 0.038), and serum ferritin levels (r = 0.516, p = 0.001). Multivariable regression analysis proved that both HbS% and serum ferritin were significant independent factors affecting sRAGE level (p < 0.05). CONCLUSION: Our findings suggest that sRAGE may be considered as a marker for vascular dysfunction in SCD patients.
