Proinflammatory phenotype can be critical in defining and modulating the genetic risk of non-syndromic hearing loss.

Non-syndromic hearing loss (NSHL) is a common sensory disorder with a multifactorial origin, involving both genetic and environmental components. Its genetic basis shows significant variability and incomplete penetrance across populations. Environmental factors, especially TORCH infections and sterile inflammation, may contribute to NSHL by triggering inflammatory cascades. Cytokines, secreted proteins crucial in immune regulation, play a central role in mediating these inflammatory responses. This study investigates whether genetic variants in cytokine genes contribute to NSHL susceptibility. A case-control genetic association study was conducted in the Malayalam-speaking Dravidian population, focusing on both pro- and anti-inflammatory cytokine gene variants. The findings reveal, for the first time, a strong association between NSHL and variants in pro-inflammatory cytokines IL1A, IFNG, IL3, and IL12B, along with the anti-inflammatory cytokine IL4. These risk variants were associated with increased pro-inflammatory activity and reduced anti-inflammatory responses. Interactome analysis showed interactions among cytokine genes IL6, IL1B, and TNF with key candidate genes such as GSDME, DIABLO, and GJA1. The results suggest an alternative NSHL pathogenesis mechanism, where environmental influences may act through cytokine gene variants to affect gene expression, possibly via a "Goldilocks effect." This study underscores the complex interplay of genetic and environmental factors in NSHL development.