ORIGINAL ARTICLE Mitochondrial DNA Haplogroups and Age-Related Hearing Loss Neil Manwaring, PhD; Michael M. Jones, MBBS; Jie Jin Wang, MMed, PhD; Elena Rochtchina, MApplStat; Chris Howard, BBiotech(Hons); Phillip Newall, MSc(Sur), MSc(Salf); Paul Mitchell, MD, PhD; Carolyn M. Sue, MBBS, PhD Objective: To determine whether variants of the mito- Results: Of the 2765 BMHS participants, 912 (33%) were chondrial genome influence the risk of developing age- found to have ARHL. After adjusting for other hearing related hearing loss (ARHL). loss risk factors, mitochondrial DNA (mtDNA) hap- logroups U and K were independently associated with a Design: Cross-sectional study. higher prevalence of ARHL compared with subjects with other haplogroups. Haplogroup U was significantly as- Setting: Eligible participants were noninstitutional- sociated with moderate to severe ARHL (multivariable- ized permanent residents 49 years or older identified in adjusted odds ratio, 1.63; 95% confidence interval, 1.10- a door-to-door census of 2 suburban postcode areas, west 2.41). Haplogroup K was associated with severity types of Sydney, Australia. of ARHL in persons aged 50 to 59 years (odds ratio, 3.02; 95% confidence interval, 1.30-6.99). There was also a joint Participants: The Blue Mountains Hearing Study effect between mtDNA haplogroups U and K and other (BMHS) was a population-based survey of hearing loss, known hearing loss risk factors such as diabetes and past conducted during 1997 to 1999, among the participants of the Blue Mountains Eye Study cohort. noise exposure. Conclusion Main Outcome Measures: We defined hearing : Findings from this older Australian popu- impairment as the pure-tone average of audiometric hear- lation demonstrate an association between certain mtDNA ing thresholds at 500, 1000, 2000, and 4000 Hz (Ͼ25- haplogroups and ARHL, as well as a link to the suscep- but Յ40-dB hearing level [HL] [mild hearing loss], tibility of other known risk factors for ARHL. Ͼ40- but Յ60-dB HL [moderate hearing loss], or Ͼ60-dB HL [severe hearing loss]) in the better of the 2 ears. Arch Otolaryngol Head Neck Surg. 2007;133(9):929-933 EARING LOSS IS THE MOST Mitochondrial DNA (mtDNA) “poly- frequent sensory disor- morphisms” are maternally transmitted and der worldwide.1 The most typically reflect different ethnic back- common form of hear- grounds. Specific mtDNA polymor- ing impairment in hu- phisms have now been classified into a mans is age-related hearing loss (ARHL, number of specific mitochondrial hap- H 2 10 also termed presbycusis), with preva- logroups. There are 10 recognized mtDNA lence estimates in Western societies rang- haplogroups within the European commu- ing between 29% and 46%.3,4 Age-related nity, 4 in the Asian community, and 1 in hearing loss is characterized by bilateral the African community. Mitochondrial high-frequency hearing loss resulting from DNA haplogroups have recently been iden- degeneration of cochlear structures within tified to be associated with a number of neu- 5 11-20 Author Affiliations: the inner ear. Both genetic and environ- rodegenerative conditions. Department of Neurogenetics, mental factors contribute causally to Rather than merely representing the Kolling Institute presence of “neutral” polymorphisms re- (Drs Manwaring, Jones, and Sue CME available online at flecting different ethnic backgrounds, dif- and Mr Howard), and www.archneurol.com ferent mtDNA haplogroups may cause Department of Ophthalmology, mild deleterious bioenergetic abnormali- Centre for Vision Research, ties. Impairment in mitochondrial func- Westmead Millennium Institute ARHL.2,5 Although age is the strongest pre- tion due to mutations in the mitochon- (Drs Wang and Mitchell and dictor for developing ARHL,6 other known drial genome (mtDNA) is associated with Ms Rochtchina), University of 3,6 Sydney, and Department of risk factors for ARHL include male sex, an insidious decline in physiologic and bio- Linguistics, Macquarie family history of hearing loss, occupa- chemical performance that contributes to 7 University (Mr Newall), tional and recreational noise exposure, the aging process and to the ultimate death Australia. type 2 diabetes mellitus,8 and smoking.9 of the organ.21 There is a growing body of (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 133 (NO. 9), SEP 2007 WWW.ARCHOTO.COM 929 ©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 evidence to suggest that ARHL may be associated with a subject was asked to return for assessment after treatment. Au- reduction in mitochondrial function.5 In keeping with diometric thresholds for air-conduction stimuli (in both ears) this, mutations in mtDNA and reduced mitochondrial were established for frequencies at 250, 500, 1000, 2000, 4000, function have been reported in human models of 6000, and 8000 Hz, with 3000 Hz added if a 20-dB difference ARHL,22,23 and mtDNA mutations have also been found existed between the 2000- and 4000-Hz thresholds. Bone con- 5,24-27 duction was evaluated whenever air conduction thresholds were in individuals with ARHL, suggesting that mtDNA greater than 15-dB hearing level (dB HL) for frequencies of 500, may play an important role in the development of ARHL. 1000, 2000, and 4000 Hz. Subjects were examined for any evi- Moreover, we have observed that hearing loss with a pat- dence of collapsed canals, and if present, air-conduction thresh- tern that is similar to that in ARHL is frequently found olds at the higher frequencies were reassessed, taking care to re- in patients with mitochondrial disease.28 duce the pressure on the external ear. For the purposes of this We hypothesized that certain mtDNA haplogroups may analysis, we defined hearing impairment as the pure-tone average increase the risk of ARHL in some individuals. We aimed of audiometric hearing thresholds at 500, 1000, 2000, and 4000 to determine whether mtDNA haplogroups are genetic Hz (Ͼ25- but Յ40-dB HL [mild hearing loss], Ͼ40- but Յ60-dB Ͼ markers for ARHL in a large representative sample of older HL [moderate hearing loss], or 60-dB HL [severe hearing loss]) Australians living in a geographically defined area, west in the better of the 2 ears. DNA was available from hair follicles and/or blood in 2856 of Sydney, Australia. of the 2956 BMHS participants (96.6%). Ninety participants, classified as having either childhood onset hearing loss (n=14), conductive hearing loss (n=58), or otosclerosis (n=18), were METHODS excluded, as was 1 participant without complete audiological data, resulting in 2765 participants (93.5%) with complete data We studied 2765 individuals from the Blue Mountains Hearing available for analysis. Study (BMHS) cohort. The BMHS was a population-based sur- Total DNA was isolated from each subject’s hair follicles vey of hearing loss conducted during thr years 1997 to 1999 among and/or blood by standard laboratory techniques.30 Ten Euro- participants of the Blue Mountains Eye Study (BMES) cohort.29 pean mtDNA haplogroups (H, I, J, K, M, T, U, V, W, and X) In 1991, we identified 4443 eligible noninstitutionalized perma- and the African superhaplogroup L were categorized by the pres- nent residents 49 years or older in a door-to-door census of 2 sub- ence or absence of the well-defined restriction enzyme recog- urban postcode areas, west of Sydney. Of this target population, nition sites as determined by polymerase chain reaction and 3654 persons (82.4%) participated in the BMES baseline survey restriction fragment length polymorphism analysis.31 (1992-1994, BMES I). During the years 1997 to 1999, 2335 of A comparison of specific mtDNA haplogroup prevalence in the 3111 survivors (75.1%) participated in 5-year follow-up ex- persons with and without hearing loss was performed using ␹2 aminations (BMES IIA). In 1999, a repeated door-to-door cen- statistics. Logistic regression analyses, adjusting for known hear- sus was conducted in the same area; 1174 of the 1378 newly eli- ing loss risk factors (age, male sex, family history, noise expo- gible residents who had moved into the study area or entered into sure at work, diabetes, and smoking) were performed to as- the study age group (85.2%) participated in BMES IIB during the sess specific mtDNA haplogroup associations with hearing loss, 1999 to 2000 period. Of these 3509 participants, 2956 (84.2%) using other haplogroups as the reference group. Further analy- also agreed to take part in the BMHS and were examined. All par- ses stratified by haplogroup explored possible interactions be- ticipants gave written informed consent and the institutional lo- tween mtDNA haplogroups and these risk factors. Odds ratios cal human ethics committees approved the study. (ORs) and 95% confidence intervals (CIs) are presented. A face-to-face interview was conducted, and a comprehen- sive medical history that included information on hearing and RESULTS lifestyle factors was obtained from all participants. An audi- ologist-administered questionnaire included demographic and socioeconomic characteristics, history of any self-perceived hear- PREVALENCE OF ARHL ing problem, including its severity, onset and duration, whether primary care practitioners or other professionals had been con- The 2765 BMHS participants in this study comprised 1574 sulted, and if a hearing aid had been provided. The medical his- women (56.9%) and 1191 men (43.1%), with a mean age tory included cardiovascular disease and risk factors, medica- of 67.4 years. Age-related hearing loss was present in 912 tions used, exercise, smoking, and caffeine or alcohol (33.0%) and was further classified as mild in 625 (22.6%), consumption. Hearing-related questions included family his- moderate in 244 (8.8%), and severe in 43 (1.6%). Se- tory of hearing loss, past medical or surgical treatment of oto- logic conditions, diseases associated with hearing loss, and risk vere hearing loss was much more frequent in men (60.5%) factors for ear disease.