title: A functional and genetic analysis of SOD2 promoter variants and their contribution to age-related hearing loss.
abstract: 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).
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Auditory Research, Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Nolan
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Cadge
authors.forename: Miriam
authors.initials: M
authors.lastname: Gomez-Dorado
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Dawson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015331:Cohort Studies; D034381:Hearing Loss / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D016329:Sp1 Transcription Factor; D013482:Superoxide Dismutase; D050656:Transcription Factor AP-2; D000099156:Superoxide Dismutase 2