تأثير تعدد الأشكال الجيني لجينَيّ ORAI1 وSTIM1 على مقاومة الارثروبويتين في المرضى العراقيين الذين يعانون من الفشل الكلوي المزمن و المعتمدين على الديلزة الدموية

The Effect of Genetic Polymorphism of STIM1 and ORAI1 Genes on Erythropoietin Resistance in Iraqi Patients with Chronic Renal Failure on Hemodialysis

Abstract
Background: Chronic renal failure is a progressive incurable disease defined as damage of kidney structure or abnormalities in kidney function for more than three months; depending on glomerular filtration rate chronic renal failure is classified into five stages. Anemia evolves during the early stages of kidney failure and exacerbates with the progression of renal disease as a result of decreased erythropoietin production. The gold standards for treating anemia in chronic renal failure are both erythropoietin-stimulating agents and iron supplementation, but the resistance to the treatment stands against its goal in many patients. ORAI1 and STIM1 are genes of store-operated calcium channels, it is one of erythropoietin activated pathway and the genetic polymorphism in those genes may contribute to erythropoietin resistance.
Aim of study: to investigate the association of genetic polymorphism in ORAI1 gene rs6486795 T> C, A and STIM1 gene rs1561876 G > A, C, T with erythropoietin resistance.
Methods: A cross-sectional observational study was carried out at Imam Al-Hussain Medical City/ Doctor Adel Al Sabbah Center for Hemodialysis in Karbala. One hundred and twelve patients both male and female, ranging in age from 20 to 79 years old being on hemodialysis and receiving epoetin alfa injection recommended weekly dose for more than 4 months, and sixty-two healthy controls were enrolled in the study as a reference for biochemical tests results. Biochemical and hematological tests were performed on each participant to determine levels of hemoglobin, erythropoietin, serum creatinine, blood urea, and iron levels. Allele-specific polymerase chain reaction technique was used to detect the rs6486795 T> C, A single nucleotide polymorphism in ORAI1 gene and the rs1561876 G > A, C, T single nucleotide polymorphism in STIM1 gene.
Results: The results obtained from the present study showed that regarding the distribution of ORAI1 gene rs6486795 among the patients enrolled the homozygous wild genotype TT represents 39.3 % of the population while the heterozygous mutant TC genotype and the homozygous mutant CC genotype represent 38.4% and 22.3% respectively. Regarding the distribution of STIM1 gene rs1561876 among the enrolled patients the predominant group is the homozygous mutant genotype AA which represents 53.6 % of the population followed by the heterozygous mutant genotype GA 29.5 % while the homozygous wild genotype GG takes the last place between groups with 17% of the population.
Conclusions: according to the results of the current study the findings revealed the genetic polymorphism of store-operated calcium channels genes ORAI1 and STIM1 were stated to be non-significantly associated with erythropoietin resistance but they cannot be excluded from the factors that contribute to erythropoietin resistance because the results showed that CC genotype in ORAI1 rs6486795 gene polymorphism has a statistically significant rise in Hb levels over TT genotype. And CCGG genotype who have the higher hemoglobin level and are considered good responders represent small portion of the patients’ population, this might explain the commonness of erythropoietin resistance among these patients.