Recent research has identified DNA sequence variants within genes encoding structural components of the collagen fibril, the basic structural unit of tendons, to modify the risk of carpal tunnel syndrome (CTS). Since the expression of these previously associated genes are regulated by cytokine and growth factor signalling pathways, the aim of this study was to determine whether variants within these cell signalling pathway genes, namely interleukin 1β (IL-1β), IL-6, interleukin 6 receptor (IL-6R) and vascular endothelial growth factor A(VEGFA), are also associated with CTS. One hundred and three self-reported Coloured participants, with a history of carpal tunnel release surgery (CTS) and 149 matched control participants (CON) without any reported history of CTS symptoms were genotyped for the functional IL-1β rs16944 (-511C/T), IL-6 rs1800795 (-174G/C), IL-6R rs2228145 (C/A) and VEGFA rs699947 (-2578C/A) variants. Only the IL-6R variant was significantly associated with CTS (p=0.005, OR=0.41, 95% CI 0.22-0.75). When the previously reported associated COL5A1 and BGN variants were included in the analysis, gene-gene interactions were also shown to significantly modulate the risk of CTS. In conclusion, the AA genotype of IL-6R rs2228145 was independently associated with reduced risk of CTS in a South African Coloured population. The IL-6R variant interacted with the previously reported COL5A1 and BGN variants to modulate CTS risk. This highlights that interleukin and growth factor gene variants should also be considered, in addition to the extracellular matrix proteins, for future research in determining the aetiology of CTS.