A functional and genetic analysis of SOD2 promoter variants and their contribution to age-related hearing loss

•−38C>G (rs5746092) and −299C>A (rs2758343) affect transcription factor binding in OC-2 cells.•Association between these rSNPs and ARHL was examined in a total of 2177 subjects.•Evidence of an association was only detected between the −38C>G SNP and ARHL.•This association was strongest in males reporting a family history of the disease.•−299C>A SNP is in complete LD with the common functional Ala(16)Val (rs4880) SNP Genetic variation in superoxide dismutase 2 (SOD2) is implicated in several ageing pathologies and with noise-induced hearing loss. Here, we have investigated the role of SOD2 promoter variants in age related hearing loss (ARHL). Putative regulatory variants identified in the SOD2 promoter using bioinformatics were functionally evaluated in an inner-ear-derived cell line (OC-2). Variants with effects on transcription factor binding were then tested in association studies in discovery and replication cohorts (London ARHL and ELSA cohorts, n=2177). The rs5746092 (−38C>G) and rs2758343 (−299C>A) SNPs alter the affinity of the SOD2 promoter for AP-2α and SP1 respectively. Evidence of an association between the −38C>G SNP and ARHL was detected in the London cohort only; p=0.0436, OR=1.35 [1.05–1.73]. This effect was strongest in males reporting family history of ARHL (p=0.0095) and was independent of reported noise exposure. The rs2758343 (−299C>A) rSNP was found to be in complete LD with the well characterised functional variant rs4880 (Ala16Val) and was not associated with hearing loss. This study describes the effect of common SOD2 promoter variation on SOD2 promoter regulation and links it to ARHL risk in men. However, due to lack of replication, this association should be regarded as suggestive only.