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Omar A Al Obeed,1 Mansoor-Ali Vaali-Mohamed,1 Khayal A Alkhayal,1 Thamer A Bin Traiki,1 Ahmad M Zubaidi,1 Maha Arafah,2 Robert A Harris,3 Zahid Khan,4,* Maha-Hamadien Abdulla1,* 1Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Department of Pathology, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 3Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 4Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia *These authors contributed equally to this work Background: IL-17 expressed by Th17 cells play a crucial role in tissue inflammation by induction of proinflammatory and neutrophil mobilizing cytokines, and IL-17 polymorphisms are associated with colorectal cancer (CRC).Objective: We investigated the expression of IL-17 and the association of IL-17 gene polymorphisms with CRC susceptibility in a Middle East population.Materials and methods: The study included 117 diagnosed CRC patients and 100 age- and gender-matched healthy controls. IL-17A rs2275913 (G197A) and IL-17F rs763780 (T7488C) single nucleotide polymorphisms, mRNA, and protein levels of IL-17A were assessed. Results: We observed significant association between rs2275913 in IL-17A and susceptibility to CRC (p = 0.016228). The AG and AA genotypes conferred 2-fold and 2.8-fold, respectively, higher risk of developing CRC compared with individuals having GG genotype. Stratification of the data based on gender and age revealed very strong association of CRC with IL17A rs2275913 only in males and “AG” genotype in patients ≤57 years of age at the time of disease diagnosis. The rs763780 in IL-17F was not linked with CRCs in our cohort. Furthermore, IL-17A mRNA expression in CRCs was significantly elevated compared to adjacent normal tissues, particularly in early stages of disease (p = 0.0005). Strong immunoreactivity to IL-17A protein was observed in 70% of early stage relative to 30% of late-stage tumors. Conclusion: The IL-17A G197A variant may be utilized as a genetic screening marker in assessing CRC risk, and its expression can be used as a biomarker for early detection of CRC in the Saudi population. Keywords: interleukin (IL), genetic polymorphism, colorectal cancer, Saudi population