The Effect of TMPRSS6 A736V Polymorphism on Hepcidin Level and Iron Metabolism in Chronic Hemodialysis Patients in Jenin City-Palestine رسالة ماجستير

Abstract

Background: Hepcidin is the principal regulator of systemic iron homeostasis. It controls dietary iron absorption and iron release from macrophages by binding to and inducing the degradation of ferroportin, the only known cellular iron exporter. Hepcidin expression is tightly regulated by body iron stores, inflammation (particularly IL-6 signaling), erythropoietic activity, and genetic factors. TMPRSS6, which encodes the serine protease matriptase-2, acts as a negative regulator of hepcidin by inhibiting the BMP/SMAD signaling pathway. In chronic hemodialysis (CHD) patients, hepcidin levels are frequently elevated due to reduced renal clearance and persistent inflammation, leading to functional iron deficiency, anemia, and increased requirements for erythropoiesis-stimulating agents and intravenous iron therapy. The TMPRSS6 rs855791 (A736V) polymorphism modulates matriptase-2 activity; the T allele has been associated with higher hepcidin expression and reduced iron availability. Objectives: To assess the impact of TMPRSS6 p.A736V on serum hepcidin levels and erythropoiesis-related parameters in Palestinian CHD patients, aiming to improve anemia management and optimize iron and drug therapy. Methods: Hematological, biochemical, and inflammatory parameters were obtained from medical records and questionnaires. Blood samples were collected for serum hepcidin measurement (ELISA) and TMPRSS6 rs855791 genotyping using allele-specific PCR. Results: Fifty CHD patients and 50 healthy controls were studied. CHD patients had significantly higher hepcidin (median 525 vs. 78.5 ng/ml, p < 0.001). The CT genotype was most common (66%), followed by CC (23%) and TT (11%), with a stepwise increase in hepcidin from CC to CT to TT. Hepcidin correlated positively with ferritin (rho = 0.302, p = 0.033) and creatinine (rho = 0.566, p < 0.001), but not with hemoglobin, MCV, RDW, or transferrin. Sex and smoking had no effect. Diabetes and hypertension were the main causes of end-stage renal disease. Conclusion: Hepcidin is elevated in CHD patients in a TMPRSS6 genotype-dependent manner. These findings underscore the need to consider TMPRSS6 variation when managing anemia and tailoring iron and erythropoiesis-stimulating therapy in CHD patients