Mitochondrial DNA Haplogroups and Age-Related Hearing Loss

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) haplogroups 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

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©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. Other questions addressed exposure to than in women (39.5%), while no sex difference was found noise at work or during military service or leisure activities and in the prevalence of mild or moderate hearing loss past use of ototoxic drugs. The severity of the noise exposure (Table 1). Age-related hearing loss was present in 116 was subjectively classified in 3 ways: mostly quiet, tolerable level, of 277 participants with diabetes (41.9%), in 392 of 1017 or unable to hear speech. The duration of the noise exposure participants who gave a history of noise exposure at work was also categorized in years. Blood pressure, height, and weight (38.5%), and in 81 of 266 participants who were cur- were measured, and body mass index was calculated. Partici- rent smokers (30.5%). pants also completed a food frequency questionnaire, which provided dietary zinc and fat intakes. PREVALENCE OF SPECIFIC Pure-tone audiometry was performed by audiologists in sound- treated booths, using standard TDH-39 earphones and Madsen mtDNA HAPLOGROUPS OB822 audiometers (Madsen Electronics, Copenhagen, Den- mark), which were calibrated regularly during the study period Of the 2765 participants, 2647 (95.7%) could be catego- to Australian standards. Testing was performed by audiologists rized into 1 of the 10 recognized European mtDNA hap- who also examined the ears for wax occlusion. If present, the logroups (H, I, J, K, T, U, V, W, X, and M) or into the

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 African’s superhaplogroup L, as shown in Table 1. Hap- logroup H was the most frequent (43.1%), followed by Table 1. Severity of Hearing Loss in the Blue Mountains haplogroups U (14.4%), J (10.6%), T (9.3%), and K Hearing Study Population Stratified by Age, Sex, Diabetes, History of Noise Exposure at Work, Current Smoking, and (7.9%). There were 118 participants (4.3%) who could Mitochondrial DNA Haplogroupa not be classified with any of the polymorphisms associated with these 11 predefined haplogroups and were des- Hearing Loss ignated as “unknown” according to standard practice.10 The distribution of mtDNA haplogroups in this study re- None Mild Moderate Severe All Subjects flected the predominantly northern European heritage Variable (n=1853) (n=625) (n=244) (n=43) (N=2765) of the population, being relatively similar to reported hap- Age, y logroup prevalence in European populations.31-33 50-59 32.7 6.7 3.3 2.3 23.8 60-69 41.3 25.4 20.5 20.9 35.6 70-79 22.8 49.0 39.8 30.2 30.3 ASSOCIATIONS WITH ARHL Ͼ80 3.2 18.9 36.5 46.5 10.3 Sex Age-related hearing loss was associated with age (OR per Male 39.6 49.3 50.8 60.5 43.1 year, 1.16; 95% CI, 1.14-1.17), male sex (OR, 1.49; 95% Female 60.4 50.7 49.2 39.5 56.9 CI, 1.21-1.82), family history of hearing loss (OR, 1.58; Diabetes 95% CI, 1.31-1.92), noise exposure at work (OR, 1.71; No 91.3 87.8 85.1 90.5 89.9 Yes 8.7 12.2 14.9 9.5 10.1 95% CI, 1.39-2.10), diabetes (OR, 1.48; 95% CI, 1.11- History of noise 1.98), and current smoking (OR, 1.55; 95% CI, 1.13- exposure at work 2.13) (Table 2). After controlling for these variables, No 66.1 57.0 60.0 39.5 63.1 we found that haplogroup U was associated with mod- Yes 33.9 43.0 40.0 60.5 36.9 erate to severe ARHL (OR, 1.63; 95% CI, 1.10-2.41) com- Current smoking Never/past 90.0 90.0 93.0 90.5 90.0 pared with other non-U haplogroups (Table 3). Al- Current 10.0 10.0 7.0 9.5 10.0 though the mean age of subjects with hearing loss did Haplogroup not vary significantly between haplogroups (range, 71.0- H 43.2 44.8 37.3 48.9 43.1 76.6 years), subgroup analysis showed that haplogroup I 2.8 2.4 2.5 2.3 2.7 K was associated with ARHL among persons aged 50 to J 10.4 11.5 9.8 11.6 10.6 59 years (OR, 3.02; 95% CI, 1.30-6.99) compared with K 7.3 9.3 8.6 9.3 7.9 non-K haplogroups. No haplogroup was associated with L 0.4 0.3 0.8 0.0 0.4 M 1.1 1.0 0.4 2.3 1.0 a reduced likelihood of having ARHL. T 9.6 8.5 10.3 4.7 9.3 The association with ARHL remained when persons with U 14.0 13.9 18.4 11.6 14.4 haplogroup K or U were grouped (cluster U/K). Subjects V 3.7 3.4 2.5 0.0 3.4 within haplogroup U/K (22% of this population) had a mod- W 2.2 1.6 2.9 0.0 2.1 erately increased risk of developing moderate to severe hear- X 0.9 0.6 0.0 2.3 0.8 ing loss (OR, 1.51; 95% CI, 1.07-2.11) compared with sub- Unknown 4.5 2.7 6.2 6.7 4.3 jects with non-U and non-K haplogroups. a Data are given as percentage of subjects. JOINT EFFECTS OF mtDNA HAPLOGROUPS AND ARHL RISK FACTORS (OR, 0.81; 95% CI, 0.54-1.23) or with moderate to severe ARHL (OR, 1.00; 95% CI, 0.53-1.90). Table 2 also shows the associations of ARHL risk factors in persons with haplogroups U, K, or others. Among persons with haplogroup U, those with diabetes had a nearly COMMENT 4-fold higher risk of moderate to severe ARHL (OR, 3.82; 95% CI, 1.42-10.26) compared with those with the same We found a significantly higher prevalence of ARHL in haplogroup but without diabetes. This risk from diabe- subjects with mtDNA haplogroups U and K. Hap- tes was higher than the similar risk among subjects with logroup U was associated with moderate to severe ARHL other haplogroups (OR, 1.67; 95% CI, 1.00-2.78) and haplogroup K was associated with ARHL in indi- (Table 2). Among persons with haplogroup K, those with viduals aged 50 to 59 years. These haplogroup associa- a history of noise exposure at work were more likely to tions were independent of other known ARHL risk fac- have any type of ARHL (OR, 2.60; 95% CI, 1.20-5.68) tors. No haplogroups were associated with reduced ARHL or moderate to severe ARHL (OR, 5.59; 95% CI, 1.42- prevalence. 21.96) than those without a past work-related noise ex- Our findings suggest that haplogroups U and K are posure (Table 2). genetic markers of ARHL susceptibility. This hypoth- Among persons with no history of noise exposure at esis is strengthened by the joint effects found between work, those with haplogroup U were more likely than these haplogroups and known ARHL risk factors: the risk those with other haplogroups to have any type of ARHL of ARHL was greater in the subgroup of persons with dia- (adjusted OR, 1.47; 95% CI, 1.04-2.07) or moderate to betes belonging to haplogroup U and in the subgroup of severe ARHL (OR, 2.26; 95% CI, 1.37-3.74). In con- persons with a history of noise exposure at work belong- trast, among persons with a history of noise exposure at ing to haplogroup K. Our results further support the con- work, haplogroup U was not associated with any ARHL cept that certain mtDNA haplogroups may cause mild

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 2. Risk Factors for Age-Related Hearing Loss (ARHL) in the Whole Study Sample and in Stratified Subgroups of Haplogroups U, K, and Othersa

Haplogroup, Any ARHL Haplogroup, Moderate to Severe ARHL

All U K Other All U K Other Risk Factor (n=912) (n=137) (n=83) (n=692) (n=287) (n=50) (n=25) (n=212) Age, per year, 1.16 (1.14-1.17) 1.19 (1.14-1.23) 1.14 (1.10-1.19) 1.16 (1.14-1.17) 1.20 (1.17-1.22) 1.25 (1.17-1.33) 1.24 (1.13-1.35) 1.19 (1.17-1.22) OR (95% CI) Male sex Subjects, No. (%) 474 (38.6) 64 (35.4) 44 (42.7) 350 (38.6) 160 (13.0) 21 (11.6) 13 (12.6) 116 (12.8) OR (95% CI) 1.49 (1.21-1.82) 1.19 (0.68-2.08) 1.11 (0.54-2.26) 1.59 (1.30-2.02) 1.68 (1.22-2.32) 1.12 (0.50-2.55) 0.86 (0.26-2.80) 1.89 (1.29-2.75) Noise exposure at work Subjects, No. (%) 405 (38.8) 57 (36.3) 33 (42.9) 302 (38.6) 132 (12.6) 18 (11.5) 10 (13.0) 96 (12.3) OR (95% CI) 1.71 (1.39-2.10) 1.18 (0.68-2.08) 2.60 (1.20-5.68) 1.75 (1.38-2.23) 1.96 (1.41-2.72) 1.21 (0.52-2.81) 5.59 (1.42-21.96) 2.00 (1.36-2.95) Diabetes Subjects, No. (%) 117 (41.9) 19 (43.2) 7 (38.9) 90 (41.9) 40 (14.3) 10 (22.7) 1 (5.6) 29 (13.5) OR (95% CI) 1.48 (1.11-1.98) 1.84 (0.88-3.87) 1.03 (0.35-3.04) 1.46 (1.05-2.02) 1.82 (1.18-2.80) 3.82 (1.42-10.26) 0.48 (0.05-4.77) 1.67 (1.00-2.78) Current smoking Subjects, No. (%) 83 (30.4) 12 (29.3) 6 (50.0) 63 (29.6) 21 (7.7) 3 (7.3) 1 (8.3) 17 (7.8) OR (95% CI) 1.55 (1.13-2.13) 1.61 (0.70-3.68) 2.32 (0.61-8.80) 1.47 (1.02-2.12) 1.56 (0.90-2.68) 1.37 (0.34-5.43) 1.50 (0.14-15.96) 1.67 (0.90-3.10) Family history of hearing loss Subjects, No. (%) 420 (33.7) 65 (35.8) 34 (35.8) 308 (33.2) 155 (12.4) 27 (14.4) 12 (12.6) 112 (12.1) OR (95% CI) 1.58 (1.31-1.92) 1.88 (1.10-3.22) 1.41 (0.73-2.70) 1.57 (1.26-1.96) 2.37 (1.75-3.21) 3.43 (1.48-7.93) 3.60 (1.05-12.26) 2.37 (1.66-3.38)

Abbreviations: CI, confidence interval; OR, odds ratio. a All models were simultaneously adjusted for age, sex, noise exposure at work, diabetes, current smoking, and family history of hearing loss.

Table 3. Associations Between the 5 Most Prevalent Mitochondrial DNA Haplogroups and Age-Related Hearing Loss (ARHL)

Mild ARHL Moderate to Severe ARHL

Age- and Multivariate Age- and Multivariate Subjects, Sex-Adjusted Adjustedb Subjects, Sex-Adjusted Adjustedb Haplogroupa No. (%) OR (95% CI) OR (95% CI) No. (%) OR (95% CI) OR (95% CI) H 280 (44.8) 1.03 (0.84-1.26) 1.01 (0.82-1.25) 112 (39.0) 0.82 (0.61-1.09) 0.79 (0.58-1.07) J 72 (11.5) 1.18 (0.86-1.62) 1.24 (0.90-1.71) 29 (10.1) 0.99 (0.61-1.58) 1.03 (0.63-1.67) K 58 (9.3) 1.15 (0.80-1.65) 1.17 (0.81-1.69) 25 (8.7) 1.00 (0.59-1.68) 1.14 (0.67-1.92) T 53 (8.5) 0.96 (0.68-1.38) 0.98 (0.69-1.41) 27 (9.4) 0.97 (0.59-1.61) 1.00 (0.60-1.67) U 87 (13.9) 1.09 (0.81-1.46) 1.05 (0.80-1.41) 50 (17.4) 1.62 (1.11-2.39) 1.63 (1.10-2.41)

Abbreviations: CI, confidence interval; OR, odds ratio. a Each haplogroup was compared with other haplogroups, such as H vs non-H haplogroups. b Adjusted for age, sex, noise exposure at work, diabetes, current smoking, and family history of hearing loss.

deleterious bioenergetic abnormalities rather than merely tween clusters UK and WIX with longevity.38 These representing the “neutral” polymorphisms reflecting dif- observations suggest that certain haplogroup clusters may ferent ethnic backgrounds. It is possible that genetic vari- modify disease susceptibility. ants in specific mtDNA haplogroups may impair respi- A strength of this study lies in its large population- ratory chain function within the cochlea to increase the based sample of participants sourced from the general risk of developing ARHL. A number of studies have sug- community, rather than an exclusively disease-specific gested associations between various mtDNA hap- group, which could potentially be subject to selection bias. logroups and a variety of medical conditions, including In this older Australian population, prevalence of ARHL Parkinson disease,11-14 Alzheimer disease,15 occipital stroke (in relation to age, male sex, hearing loss severity, and in migraine,16 Leber hereditary optic neuropathy,17-19 and other known risk factors) and of each mtDNA hap- multiple sclerosis.20 Of particular interest, haplogroup U logroup were similar to data reported from studies of Eu- has previously been associated with occipital stroke,34 azo- ropean and North American populations,3,4,10,32,33 sug- ospermia,35 and Alzheimer disease.15 gesting that our results would likely be applicable to other Although initially recognized as a separate hap- white-based societies. logroup, haplogroup K is regarded as a subgroup, or hap- In conclusion, our findings suggest that mtDNA haplotype, of U itself by some researchers.36,37 A similar logroups U and K are independent genetic markers for mtDNA haplogroup cluster analysis showed a protec- moderate to severe ARHL and may modify susceptibil- tive association of cluster UKJT with Parkinson dis- ity associated with some known risk factors. Mitochon- ease,13 and other studies have shown an association be- drial DNA may play a role in the pathogenesis of ARHL,

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 but our findings need to be corroborated by future stud- mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction re- ies to confirm the prevalence of mtDNA haplogroups in sulting in an increased risk of Parkinson’s disease in the Irish. Exp Gerontol. 2003; 38(4):397-405. other populations of individuals affected with ARHL. The 13. Pyle A, Foltynie T, Tiangyou W, et al. Mitochondrial DNA haplogroup cluster UKJT precise mechanism underlying how mtDNA hap- reduces the risk of PD. Ann Neurol. 2005;57(4):564-567. logroups increase genetic risk for ARHL remains to be 14. van der Walt JM, Nicodemus KK, Martin ER, et al. Mitochondrial polymor- clarified. If these findings are confirmed, introduction of phisms significantly reduce the risk of Parkinson disease. Am J Hum Genet. 2003; preventive strategies to minimize environmental causes 72(4):804-811. 15. van der Walt JM, Dementieva YA, Martin ER, et al. Analysis of European mito- could be implemented to reduce the overall risk of a ge- chondrial haplogroups with Alzheimer disease risk. Neurosci Lett. 2004;365 netically susceptible individual of developing ARHL. (1):28-32. 16. Majamaa K, Finnila S, Turkka J, Hassinen IE. Mitochondrial DNA haplogroup U Submitted for Publication: August 9, 2006; final revi- as a risk factor for occipital stroke in migraine. Lancet. 1998;352(9126): sion received May 10, 2007; accepted May 14, 2007. 455-456. 17. Sadun F, De Negri AM, Carelli V, et al. Ophthalmologic findings in a large pedi- Correspondence: Carolyn M. Sue, MBBS, PhD, Depart- gree of 11778/Haplogroup J Leber hereditary optic neuropathy [published cor- ment of Neurogenetics, Clinic 4, Royal North Shore Hos- rection appears in Am J Ophthalmol. 2004;137(4):following 793]. Am J Ophthalmol. pital, Reserve Road, St Leonards, New South Wales, Aus- 2004;137(2):271-277. tralia 2065 ([email protected]). 18. Brown MD, Starikovskaya E, Derbeneva O, et al. The role of mtDNA background Author Contributions: Dr Sue had full access to all the in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup Hum Genet. 2002;110(2):130-138. data in the study and takes responsibility for the integ- 19. Howell N, Herrnstadt C, Shults C, Mackey DA. Low penetrance of the 14484 LHON rity of the data and the accuracy of the data analysis. Study mutation when it arises in a non-haplogroup J mtDNA background. Am J Med concept and design: Mitchell and Sue. Acquisition of data: Genet A. 2003;119(2):147-151. Manwaring, Wang, Howard, Newall, and Sue. Analysis 20. Kalman B, Li S, Chatterjee D, et al. Large scale screening of the mitochondrial and interpretation of data: Jones, Wang, Rochtchina, and DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians. Acta Neurol Scand. 1999;99(1):16-25. Sue. Drafting of the manuscript: Manwaring, Jones, Newall, 21. Nagley P, Wei YH. Ageing and mammalian mitochondrial genetics. Trends Genet. and Sue. Critical revision of the manuscript for important 1998;14(12):513-517. intellectual content: Jones, Wang, Rochtchina, Howard, 22. Keithley EM, Harris B, Desai K, et al. Mitochondrial cytochrome oxidase immu- and Mitchell. Statistical analysis: Rochtchina. Obtained nolabeling in aged human temporal bones. Hear Res. 2001;157(1-2):93-99. funding: Wang, Newall, Mitchell, and Sue. Administra- 23. Dai P, Yang W, Jiang S, et al. Correlation of cochlear blood supply with mitochondrial DNA common deletion in presbyacusis. Acta Otolaryngol. 2004;124 tive, technical, and material support: Manwaring and (2):130-136. 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