a case-control study of tobacco and alcohol consumption in leber hereditary optic neuropathy
TRANSCRIPT
A Case-control Study of Tobacco and AlcoholConsumption in Leber Hereditary Optic
Neuropathy
JOHN B. KERRISON, MD, NEIL R. MILLER, MD, FANG-CHI HSU, MS, TERRI H. BEATY, PHD,IRENE H. MAUMENEE, MD, KYLE H. SMITH, MD, PETER J. SAVINO, MD,
EDWIN M. STONE, MD, PHD, AND NANCY J. NEWMAN, MD
● PURPOSE: To determine if tobacco or alcohol con-sumption is associated with vision loss among sibshipsharboring pathogenic mitochondrial mutations associatedwith Leber hereditary optic neuropathy.● METHODS: Retrospective case-control study with ques-tionnaires obtained from both affected and unaffectedsiblings from 80 sibships with Leber hereditary opticneuropathy. Sibships harbored molecularly confirmedmitochondrial DNA mutations at nucleotide positions11778 (63), 14484 (10), and 3460 (7). Exposure inaffected individuals was calculated based on reportedconsumption before vision loss.● RESULTS: For male probands (67 sibships), the recur-rence risk within a sibship was 10.3% (eight of 78) formales and 3.1% (three of 98) for females. For femaleprobands (13 sibships), the recurrence risk within asibship was 17.6% (three of 17) for males and 0% (zeroof 22) for females. Greater risk of vision loss wasassociated with male sex (odds ratio [OR] 5 6.63; 95%confidence interval [CI] 5 2.96 to 14.84; P 5 .00001)and harboring a 3460 or 14484 in comparison with the11778 mutation (OR 5 2.071; 95% CI 5 1.19 to 3.58;P 5 .0095). No significant association of maximalintensity of smoking or cumulative smoking, whetherlight or heavy, with vision loss was observed. Light(OR 5 0.31; 95% CI 5 0.17 to 0.56; P 5 .0001) and
heavy alcohol consumers (OR 5 0.25; 95% CI 5 0.11to 0.58; P 5 .0011) were less likely to be affected thanindividuals who did not consume alcohol after adjustingfor age, sex, and mutation. In a categorical analysis ofsibships with the 3460 or 14484 mutation, no relation-ship of vision loss with tobacco or alcohol consumptionwas observed.● CONCLUSION: Unlike previous studies, the presentstudy calculated exposure based on self-reported con-sumption of tobacco or alcohol before vision loss. Nosignificant deleterious association between tobacco oralcohol consumption and vision loss among individualsharboring Leber hereditary optic neuropathy mutationswas observed. Tobacco and alcohol do not appear topromote vision loss in Leber hereditary optic neuropathy.(Am J Ophthalmol 2000;130:803–812. © 2000 byElsevier Science Inc. All rights reserved.)
L EBER HEREDITARY OPTIC NEUROPATHY IS A BILAT-
eral optic neuropathy caused by point mutations inthe mitochondrial genome. Primary mutations are
located at nucleotide positions 3460,1 11778,2,3 and144844 in genes encoding various subunits of complex I ofthe respiratory chain.
Despite identification of the molecular basis of Leberhereditary optic neuropathy, several clinical features andfactors influencing penetrance remain poorly understood.Unexplained clinical features include the acute onset, lackof repeated episodes of vision loss, and late improvementin visual acuity in some cases. Unexplained observationsregarding disease penetrance include the fact that men aremore frequently affected with visual loss than women,comprising 80% to 90% of patients in case series.3,5,6
Although all offspring inherit the mitochondrial DNAmutation, not all offspring develop vision loss. Given thenon-Mendelian inheritance and the lack of understandingof factors influencing disease penetrance, counseling ofindividuals harboring a pathogenic mitochondrial muta-tion regarding the risk of vision loss can be based only on
Accepted for publication June 5, 2000.From the Wilmer Ophthalmological Institute, Johns Hopkins Hospital
(Drs Kerrison, Miller, and Maumenee), Baltimore, Maryland; the Schoolof Public Health, Johns Hopkins University (Drs Hsu and Beaty),Baltimore, Maryland; Scott & White Hospital (Dr Smith), Temple,Texas; Wills Eye Hospital (Dr Savino), Philadelphia, Pennsylvania; theDepartment of Ophthalmology, Iowa University Hospitals (Dr Stone),Iowa City, Iowa; the Department of Ophthalmology, Neurology, andNeurological Surgery, Emory University School of Medicine (Dr New-man), Atlanta, Georgia.
This work was supported by a grant from the Heed Foundation,Cleveland, Ohio (Dr Kerrison) and the Lewis R. Wasserman Award (DrNewman) from Research to Prevent Blindness, Inc, New York, New York.
Requests for reprints to John B. Kerrison, MD, Wilmer Ophthalmo-logical Institute, 600 North Wolfe St, Baltimore, MD 21287; fax: (410)614-9632; e-mail: [email protected]
© 2000 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED.0002-9394/00/$20.00 803PII S0002-9394(00)00603-6
empirical observations. In an analysis of 85 Leber heredi-tary optic neuropathy families with the exclusion of indexcases, the best estimate of recurrence risk among sibshipswas 30% to brothers and 8% to sisters of index cases.7
Whereas mitochondrial mutations are required for Leberhereditary optic neuropathy disease expression, other ge-netic and epigenetic factors are believed to play a role indisease penetrance and expression. Proposed genetic mod-ifiers of disease penetrance include heteroplasmy,8 anX-linked vision loss susceptibility locus,9–16 nuclear en-coded genes,17 and secondary mitochondrial DNA muta-tions.18 Environmental exposures of particular interestinclude occupational exposures,19 tobacco smoking,20,21
and alcohol consumption.21 Because no treatments forvision loss in patients with symptomatic Leber hereditaryoptic neuropathy are available, it would be beneficial toidentify modifiable exposures that promote vision loss inat-risk individuals. The purpose of the present study was toexamine, using a case-control design, the influence oftobacco and alcohol consumption on the development ofvision loss within sibships harboring pathogenic mito-chondrial DNA mutations. Unaffected siblings were usedas controls, assuming that all siblings harbor the samemitochondrial DNA mutation and are therefore at risk forvision loss.
METHODS
PATIENTS WITH A MOLECULARLY CONFIRMED DIAGNOSIS
of Leber hereditary optic neuropathy were ascertained fromclinic records of the Wilmer Eye Institute, Scott andWhite Hospital, Wills Eye Hospital, Emory Eye Center,and from the Genetic Eye Diseases Registry of the Uni-versity of Iowa. Patients had either the 3460, 11778, or14484 mitochondrial DNA mutations. Unaffected siblingsgenerally did not undergo genetic testing but were as-sumed, based on the principles of mitochondrial genetics,to harbor a Leber hereditary optic neuropathy mutationand be at risk for vision loss. Clinic patients were con-tacted by telephone to describe the study and ask them ifthey were willing to participate. Patients who were ascer-tained through the lab were initially contacted by theirprimary physician. With a patient’s verbal consent, thesiblings were contacted. Family members who agreed toparticipate were sent a questionnaire and a consent formapproved by the institutional review boards of JohnsHopkins Hospital, University of Iowa Hospitals, or EmoryUniversity School of Medicine. If a sibling reported thathe or she had abnormal vision and had been diagnosedwith Leber hereditary optic neuropathy, he or she wasconsidered affected. Questionnaires and consent formssent to affected individuals were in large type to facilitatecompletion. Stamped return envelopes were provided.
Basic demographic data asked in the questionnaireincluded age, birthday, sex, race, marital status, number of
siblings, number of male siblings, and number of femalesiblings.
Questions about smoking history included whether theyhad smoked more than 100 cigarettes in their lifetime, theage at which they started smoking, the average initialsmoking consumption (cigarettes per day), if there hadbeen a change in smoking consumption (increase, de-crease, no change, stop), the age at change in smokingconsumption, and the average smoking consumption sincechange (cigarettes per day). Similar questions were askedwith regard to pipe and cigar smoking.
Questions about alcohol consumption included whetherthey had ever consumed alcohol more frequently than onedrink a month, the age at the start of alcohol consumption,whether they drank primarily beer, wine, or liquor,whether they regularly consumed more than one type ofalcoholic beverage, the average initial number of drinksper week, if there had been a change in consumption(increase, decrease, no change, stop), the age at change inalcohol consumption, and the average number of drinksper week since change. If they consumed more than onetype of alcoholic beverage, a similar series of questions wasasked for each type.
Specific questions regarding vision and some pertinentquestions regarding Leber hereditary optic neuropathywere asked: Do you have normal vision? Do you haveLeber hereditary optic neuropathy? At what age did youstart to lose vision? Have you had improvement in yourvision? Has your mother lost vision because of Leberhereditary optic neuropathy?
Other areas of questioning included diet, past medicalhistory, medications, vitamin consumption, employment,occupation, and potential environmental exposures.
Cumulative smoking was calculated in packs per daytimes the number of years of smoking (pack years).Maximum intensity of smoking was determined by whichwas greater, initial smoking or smoking after a change inconsumption. Both cumulative smoking in pack years andmaximum intensity of smoking in packs per day wereanalyzed as continuous variables. No smoking, smokingless than the seventy-fifth percentile for the entire group ofsmokers (light smoking), and smoking greater than theseventy-fifth percentile for the entire group of smokers(heavy smoking) were considered in a categorical analysisof cumulative smoking and maximum intensity of smok-ing. Of particular importance in determining whethersmoking contributes to vision loss in susceptible individu-als was their smoking exposure before losing vision. There-fore, cumulative smoking in affected individuals wascalculated as the exposure before vision loss. In thoseaffected individuals who began smoking after vision loss,cumulative smoking exposure was considered to be zero.Age of onset of vision loss relative to the age at the startor change in smoking was also taken into consideration inthe determination of maximal intensity of smoking.
Calculation of alcohol consumption was based on the
AMERICAN JOURNAL OF OPHTHALMOLOGY804 DECEMBER 2000
combined consumption of beer, wine, and liquor. As withtobacco consumption, both cumulative alcohol consump-tion in drinks per week times the number of years ofdrinking (drink years) and maximum intensity of alcoholconsumption in drinks per week were analyzed as contin-uous variables and categorically, based on the seventy-fifthpercentile cutoff for the entire group of alcohol consumers.Individuals who began drinking after losing vision wereconsidered to have an exposure of zero. As no positivecorrelation was observed, the calculation of exposure toalcohol in drink years before vision loss was not performed.
Analysis was performed using the GENMOD procedurein the SAS software (Cary, North Carolina) on the sibshipdataset, which included only sibships with a returnedquestionnaire from at least one affected and one unaffectedmember. All models controlled for age, sex, and mutation.Mutation type was adjusted for by comparing those withthe 11778 mutation with those harboring the 3460 or14484 mutations. The Kaplan Meyer survival curve wascalculated using the LIFETEST procedure in SAS. Recur-rence risk was calculated as the frequency of being affectedamong siblings of index cases.
RESULTS
ONE HUNDRED FIFTY-THREE LEBER HEREDITARY OPTIC NEU-
ropathy probands from different families were identified.We were unable to contact 58 Leber hereditary opticneuropathy probands. Ninety-five Leber hereditary opticneuropathy probands, from 95 families, agreed to partici-pate, and questionnaires were sent to them and theirsiblings. Of these 95 families, at least one questionnairewas returned from 87 families, which included siblings ofthe proband as well as aunts and uncles if a member of thepreceding generation had experienced vision loss. Eightynine percent of individuals within each family completedquestionnaires. A total of 261 questionnaires were re-turned, 103 from affected individuals and 158 from unaf-fected individuals.
For the 87 families at risk for vision loss, the averagenumber of individuals per sibship was 3.47 (Table 1).Three of the probands had no siblings. The overallaverage age was 40.15 years (range, 8 to 79; SD 613.87) with a male-to-female ratio of 0.92. Each sibshiphad an average of 1.16 affected individuals and 2.31unaffected individuals.
Of the 87 families, 77 families, incorporating 80 sib-ships, returned two or more questionnaires, including onefrom an affected and one from an unaffected sibling. These80 sibships were the subject of further analysis. Among the80 sibships, the recurrence risk of vision loss was assessed(Table 2). Sixty-seven of the sibships had only oneaffected member. For male probands (67 sibships), theoverall recurrence risk of vision loss for male siblings was10.3% (eight of 78) and for female siblings was 3.1% (three
of 98). For female probands (13 sibships), the recurrencerisk of vision loss for male siblings was 17.6% (three of 17)and for female siblings was 0% (zero of 22). In eightsibships, the mother of an affected individual had experi-enced vision loss. Of 80 sibships, 63 harbored the 17778mutation, seven harbored the 3460 mutation, and 10harbored the 14484 mutation.
The average age of onset of vision loss per sibship was29.74. In five of 80 sibships, an affected individual lostvision before age 14.
Age, sex, and mutation were used in all models (Table3). Age was not statistically significant in any model. Malegender was a statistically significant risk factor for visionloss in all models (OR 5 6.63; 95% CI 5 2.96 to 14.84;P 5 .00001). A Kaplan-Meyer survival curve demon-strated that males are more likely to lose vision in familiesharboring Leber hereditary optic neuropathy causing mi-tochondrial DNA mutations (Figure 1). With regard tomutation, individuals were categorized as having the11778 mutation versus the 3460 or 14484 mutation.Previous studies have suggested that the susceptibility ofpatients to vision loss with the latter two mutations maydiffer from those with the more common 11778 muta-tion.21 Individuals with the 3460 or 14484 mutation were
TABLE 1. Demographics of Families Participating in Study
Mean 6 SD (range)
Families returning at least one
questionnaire
87
Families returning two or more
questionnaires (at least one affected
and one unaffected sibling)
77
Sibships returning two or more
questionnaires (at least one affected
and one unaffected sibling)
80
Number of siblings per sibship 3.47 6 1.85 (2–10)
Affected individuals per sibship 1.16 6 0.40 (1–3)
Unaffected individuals per sibship 2.31 6 1.76 (1–9)
Participants per sibship 3.04 6 1.24 (2–8)
Percent of participants per sibship 89 6 1.7%
Ratio of males to females per sibship 0.92 6 0.61
Age at time of study 40 6 13.87 (8–79)
Age of onset of vision loss 29.74 6 14.49 (2–73)
Number of sibships with vision loss
before age 14
5/80
TABLE 2. Recurrence Risk of Vision Loss Among 80Sibships with Leber Hereditary Optic Neuropathy
Probands
Risk of Recurrence
in Male Sibling
Risk of Recurrence
in Female Sibling
Male probands (67) 10.3% (8 of 78) 3.1% (3 of 98)
Female probands (13) 17.6% (3 of 17) 0% (0 of 22)
LEBER HEREDITARY OPTIC NEUROPATHYVOL. 130, NO. 6 805
2.071 times more likely to be affected in comparison withindividuals having the 11778 mutation after adjusting forage and sex (OR 5 2.07; 95% CI 5 1.19 to 3.58; P 5.0095). Kaplan-Meyer survival curve demonstrated nodifference in the age of onset in comparing patients withthe 3460, 11778, and 14484 mutations (Figure 2).
Of a total 103 affected individuals returning question-naires, 56 (54.4%) had smoked at least 100 cigarettes.Eight of these 56 individuals lost vision before beginningto smoke. Twenty-one of 80 sibships (26.3%) did not haveany cigarette smokers (Table 4). Among the remainingsibships, the average number of smokers per sibship was1.56. The average age of onset of smoking was 17. Theaverage initial consumption per smoker within a sibshipwas approximately half a pack of cigarettes a day. Themaximum amount of smoking by an individual was threepacks per day. Initial analysis of cumulative smokingdemonstrated a significant association with vision loss, inparticular for those in the upper quartile (OR 5 3.67; 95%CI 5 1.41 to 9.55; P 5 .0077).
Further analysis was performed after consideration of theage of onset of vision loss relative to smoking (Table 5). Inthis analysis, individuals who lost vision before smokinghad a smoking exposure of zero, and individuals who hadsmoked before vision loss had their cumulative smokingcalculated as their exposure before the age of vision loss.After this consideration, the seventy-fifth percentile forcumulative smoking was 16 pack years. The seventy-fifthpercentile for maximum intensity of smoking was one packper day. Using a model that included age, sex, andmutation and took into consideration the correlationalstructure within each sibship, no significant association ofvision loss with cumulative smoking, whether light orheavy, or maximum intensity of smoking, whether at onsetor subsequent change, was observed. Table 6 demonstratesthe percentages of affected and unaffected individualswithin each category of smoking. Survival analysis failed todemonstrate a relation between categories of tobaccoexposure and age of onset of vision loss (Figure 3).
After accounting for age, separate analysis of the 17
pedigrees harboring either the 3460 or 14484 mutationdemonstrated a statistically significant relationship be-tween the maximum intensity of smoking, measured as acontinuous variable, and vision loss (P 5 .0184). However,categorical analysis of maximum intensity of smoking aslight or heavy smoking demonstrated no relationship(Table 7). No association of cumulative smoking, assessedas both a continuous variable or categorically, with visionloss was observed.
Because only 11 sibships had at least one pipe or cigarsmoker, insufficient data were available for analysis.
Of a total of 103 affected individuals returning question-naires, 79 had consumed alcohol more frequently than onedrink a month. Fifteen of 79 affected individuals begandrinking after loss of vision. Three of 80 sibships did nothave any alcohol consumers (Table 3). Among remainingsibships, the average number of alcohol consumers was2.35. The average age of onset of alcohol consumption was19.35. The average initial alcohol consumption per drinkerwithin a sibship was 11.6 drinks per week. After consider-ation of the age of onset, the seventy-fifth percentile forcumulative alcohol consumption was 216 drink years. Theseventy-fifth percentile for maximum intensity of alcoholconsumption was 15 drinks per week. Maximum intensityof alcohol consumption, whether at the start of drinking orafter a change in consumption, and cumulative drinking,after adjusting for age of onset of vision loss relative to ageof onset of drinking, were assessed. In both instances, lightalcohol consumers were less likely to be affected thanindividuals who did not consume alcohol after adjustingfor age, sex, and mutation (Table 5). Furthermore, heavyalcohol consumers were less likely to be affected whencompared with individuals who did not consume alcoholafter adjusting for age, sex, and mutation. Table 6 demon-strates the percentages of affected and unaffected indi-viduals within each category of alcohol consumption.Survival analysis failed to demonstrate a relation betweencategories of alcohol exposure and age of onset of visionloss (Figure 4).
Separate analysis of the 17 pedigrees harboring eitherthe 3460 or 14484 mutation demonstrated no statisti-cally significant relationship between the maximumintensity or cumulative alcohol consumption with vi-sion loss (Table 7).
DISCUSSION
THE POSSIBILITY THAT AN ENVIRONMENTAL FACTOR
could trigger vision loss in susceptible patients with Leberhereditary optic neuropathy has been based on the hypoth-esis that vision loss is linked to defects in oxidativephosphorylation such that beyond a bioenergetic thresh-old, a cell’s ability to respond to damage is impaired. Notonly are Leber hereditary optic neuropathy mutationsassociated with a lower mitochondrial complex I activity,22
TABLE 3. Analysis of Age, Sex, and Mutation
Odds Ratio
95% Confidence
Interval P Value
Age 0.999 0.981–1.017 .9719
Sex 6.635 2.966–14.842 .00001
Mutation 2.070 1.194–3.588 .0095
GENMOD analysis of age, sex, and mutation demonstrates
that male gender and inheritance of mitochondrial DNA muta-
tions at nucleotide positions 3460 or 14484 in comparison with
inheritance of a mitochondrial DNA mutation at nucleotide
position 11778 were associated with greater odds of vision loss
among individuals at risk for Leber hereditary optic neuropathy.
AMERICAN JOURNAL OF OPHTHALMOLOGY806 DECEMBER 2000
but cigarette smoking decreases mitochondrial complex Iactivity.23 It has thus been postulated that reduced com-plex I activity caused by exposure to toxins, which can betolerated by normal individuals, causes vision loss inindividuals harboring a pathogenic Leber hereditary opticneuropathy mutation. Once optic atrophy ensues, thebioenergetic demand is lowered, thus explaining whypatients would not develop further loss.
Anecdotal reports and case series seem to support thishypothesis. For example, some patients with Leber hered-itary optic neuropathy experience a traumatic or metabolicinsult preceding vision loss.1,4,24 Rizzo25 described a patientwith bilateral optic neuropathy who had vitamin B12deficiency and the mtDNA 14484 mutation in whomvision improved to 20/20 after treatment. Monozygotictwins discordant for vision loss associated with mtDNAmutations have been reported.19,26 In clinical series, the
prevalence of alcohol consumption has ranged from 14%to 67% and for tobacco consumption from 46% to75%.1,3,4,6 A series of patients diagnosed with tobacco-alcohol amblyopia were subsequently determined to haveLeber hereditary optic neuropathy by molecular genetictesting.27 These reports suggested that a metabolic insultmay contribute to vision loss in susceptible patients.
Evidence against an environmental trigger includes theobservations that widespread nutritional deficiency inCuba did not appear to increase the risk of vision loss in alarge pedigree harboring the mtDNA 11778 mutation.28
Monozygotic twins concordant for vision loss have alsobeen reported.29,30 In fact, one report of discordanceamong monozygotic twins19 was later followed up with areport of subsequent vision loss in the other twin.31
Furthermore, molecularly confirmed Leber hereditary opticneuropathy has been reported in patients as young as 5
FIGURE 1. Survival analysis with regards to gender. Kaplan-Meyer survival curve demonstrates that males are more likely to losevision in families harboring Leber hereditary optic neuropathy causing mitochondrial DNA mutations. Around age 42, 50% of menare affected, whereas only 15% of women are affected. The two curves are statistically significant by log-rank test (P 5 .0001).
FIGURE 2. Survival analysis with regards to mutation. Kaplan-Meyer survival curve demonstrates no difference in the unaffectedrates in comparing patients with the 3460, 11778, and 14484 mutations (P 5 .3379 by log-rank test).
LEBER HEREDITARY OPTIC NEUROPATHYVOL. 130, NO. 6 807
years of age,32 which suggests that visual loss in childrenwith a Leber hereditary optic neuropathy mutation may betriggered by factors different from those that trigger visualloss in young adults.
Two studies have examined the causal relationshipbetween the development of vision loss and exposure tocigarettes or alcohol in Leber hereditary optic neuropa-thy.20,21 Tsao and associates20 reported a single pedigree
TABLE 4. Cigarette Tobacco and Alcohol Consumption in Families With Leber HereditaryOptic Neuropathy
Mean 6 SD (range)
Cigarette consumption
Sibships with no smokers 21/80
Smokers per sibship 1.56 6 1.34 (0–6)
Age of onset of smoking per sibship 17.02 6 2.02 (10–21) years
Average initial cigarette consumption per smoker
within a sibship
8.55 6 4.47 (1–20) cigarettes/day
Seventy-fifth percentile for cumulative smoking
among smokers*
16 pack years
Seventy-fifth percentile for maximum intensity of
smoking among smokers*
1 pack/day
Average cumulative smoking per smoker within a
sibship*
5.26 6 7.65 (0–44.85) pack years
Average maximum intensity of per smoker within
a sibship*
0.30 6 0.31 (0–1.10) packs/day
Alcohol consumption
Number of sibships with no drinkers 3/80
Number of drinkers per sibship 2.35 6 1.34 (0–7)
Age of onset of drinking per sibship 19.35 6 3.38 (14–40) years
Average initial alcohol consumption per drinker
within a sibship
11.57 6 10.51 (1–54) drinks/week
Seventy-fifth percentile for cumulative drinking
among drinkers*
216 drink years
Seventy-fifth percentile for maximum intensity of
drinking among drinkers*
15 drinks/week
Average cumulative drinking per drinker within a
sibship*
146.07 6 188.53 (0–840) drink years
Average maximum intensity of drinking per
drinker within a sibship*
10.81 6 11.06 (0–58) drinks/week
*After considering those who began smoking or drinking after vision loss as nonsmokers or
nondrinkers.
TABLE 5. Analysis of the Risk of Vision Loss Relative to Cigarette Tobacco and Alcohol Consumption in 80 Sibships With LeberHereditary Optic Neuropathy Assessed With Consideration of the Age of Onset of Smoking or Drinking Relative to the Age of
Onset of Vision Loss
Odds Ratio
95% Confidence
Interval P Value
Maximum intensity of tobacco consumption , 75th percentile 1.119 0.607–2.061 .7182
$ 75th percentile 1.466 0.602–3.566 .3989
Cumulative tobacco consumption , 75th percentile 1.406 0.553–2.350 .7213
$ 75th percentile 1.649 0.843–3.222 .1433
Maximum intensity of alcohol consumption , 75th percentile 0.3140 0.174–0.566 .0001
$ 75th percentile 0.2573 0.113–0.583 .0011
Cumulative alcohol consumption , 75th percentile 0.3087 0.158–0.601 .0005
$ 75th percentile 0.4754 0.214–1.055 .0678
Each group is compared with nonconsumers of tobacco or alcohol.
AMERICAN JOURNAL OF OPHTHALMOLOGY808 DECEMBER 2000
FIGURE 3. Survival analysis of maximal intensity and cumulative smoking. (Top) Kaplan-Meyer survival curve with regard tointensity of smoking before vision loss demonstrates no difference in the unaffected rates in comparing nonsmokers, light smokers,and heavy smokers (P 5 .8481 by log-rank test). (Bottom) Kaplan-Meyer survival curve with regard to cumulative smokingdemonstrates no difference in the unaffected rates in comparing nonsmokers, light smokers, and heavy smokers (P 5 .3156 bylog-rank test). The three curves cross over each other. Before age 60, the ages of onset among light smokers are older. If smokingpromoted vision loss, one might expect to observe a younger age of onset among smokers.
TABLE 6. Percentages of Affected and Unaffected Individuals Within Each Category of Tobacco and Alcohol Consumption
Affected Males
(n 5 78)
Unaffected Males
(n 5 66)
Affected Females
(n 5 16)
Unaffected Females
(n 5 89)
Maximum intensity of tobacco consumption None 45.83 48.48 46.67 57.30
, 75th percentile 36.11 34.85 26.67 26.97
$ 75th percentile 18.06 16.67 26.67 15.73
Cumulative tobacco consumption None 49.28 48.48 46.67 57.95
, 75th percentile 37.68 37.88 40.00 29.55
$ 75th percentile 13.04 13.64 13.33 12.50
Maximum intensity of alcohol consumption None 27.54 13.64 50.00 34.52
, 75th percentile 39.13 62.12 42.86 58.33
$ 75th percentile 33.33 24.24 7.14 7.14
Cumulative alcohol consumption None 31.75 14.29 50.00 35.8
, 75th percentile 44.44 58.73 42.86 50.62
$ 75th percentile 23.81 26.98 7.14 13.58
LEBER HEREDITARY OPTIC NEUROPATHYVOL. 130, NO. 6 809
with 65 family members harboring the 11778 mutation inwhich cigarette exposure among affected and unaffectedindividuals was compared at ages 25 and 35. All symptom-atic individuals in this family were smokers, whereas 25%to 42% of unaffected individuals were smokers. This resultwas influenced by the fact that the cutoff for categorizationof individuals as smokers was the minimum amount ofsmoking by patients with Leber hereditary optic neuropa-thy. However, this suggested that, at least in this family, agreater percentage of symptomatic patients were smokers.Chalmers and Harding21 examined cigarette and alcoholconsumption in 50 patients with Leber hereditary opticneuropathy who had mutations at 11778, 3460, and 14484compared with a group of controls. Consumption oftobacco and alcohol was not statistically different for
patients with the 11778 mutation but was increased in asubgroup of patients with either the 3460 or 14484 mutation.Half of their controls were unrelated to the patient, makinginterpretation of the study difficult. In neither study wasconsideration of exposure before onset of vision loss used inthe analysis. This consideration is essential in the assessmentof whether exposure to tobacco or alcohol promotes visionloss in Leber hereditary optic neuropathy.
The present study assessed smoking and alcohol con-sumption in 80 sibships where all individuals were presum-ably at risk for vision loss. Unlike previous studies, thepresent analysis accounted for the age of onset of visionloss relative to the onset of smoking or drinking. Wedemonstrated that smoking, maximum intensity of smok-ing, and cumulative smoking were not risk factors for
FIGURE 4. Survival analysis of maximal intensity and cumulative drinking. (Top) Kaplan-Meyer survival curve with regard tointensity of drinking before vision loss demonstrates that non–alcohol drinkers, light alcohol drinkers, and heavy alcohol drinkershave different time to onset of vision loss (P 5 .0165 by log-rank test). The three curves cross over each other. Light alcoholdrinkers are almost always less likely to lose vision in comparison with the other two groups. Before age 40, non–alcohol drinkersare more likely to lose vision compared with heavy alcohol drinkers. Survival bias may be an explanation in that longer survival isassociated with greater cumulative drinking. Therefore, we may find more heavy alcohol drinkers who lose their vision at older ages.(Bottom) Kaplan-Meyer survival curve with regard to cumulative drinking before vision loss demonstrates no difference in theunaffected rates in comparing non–alcohol drinkers, light alcohol drinkers, and heavy alcohol drinkers (P 5 .1772 by log-rank test).The three curves cross over each other. Before age 50, light alcohol drinkers are less likely to be affected.
AMERICAN JOURNAL OF OPHTHALMOLOGY810 DECEMBER 2000
vision loss in individuals harboring Leber hereditary opticneuropathy–associated mitochondrial mutations.
Subgroup analysis of individuals harboring a 3460 or14484 mutation demonstrated a relationship between vi-sion loss and maximum intensity of smoking as a contin-uous variable. However, this should be interpreted withcaution, given the small number of sibships involved inthis analysis and the finding that, with regard to maximumintensity of smoking, neither heavy smoking nor lightsmoking in comparison with no smoking was associatedwith vision loss. Furthermore, no relationship betweencumulative smoking and vision loss was observed. Al-though it might be assumed that each primary Leberhereditary optic neuropathy mutation has a similar patho-physiology, because all known primary mutations affectvarious subunits of complex I, they each have differentbiochemical profiles and result in phenotypic differenceswith regards to recovery of vision.33 Thus, further studiesare required to determine whether there is a relationshipbetween smoking and vision loss for the two less commonprimary mutations.
We demonstrated that both light alcohol consumptionand, to a lesser extent, heavy alcohol consumption weremore common among unaffected individuals. This wasobserved in both cumulative and cross-sectional analysis.This contrasts with the observation of Chalmers andHarding.21 The observed effect is likely secondary to themethod of calculating exposure in affected individuals ormay reflect underreporting of alcohol consumption byaffected individuals in the present study. Nevertheless, thisresult suggests that alcohol consumption does not promotevision loss in Leber hereditary optic neuropathy.
Our study was subject to a recall bias as well as a bias ofascertainment. Recall bias may be playing a role, becausesome patients had to recall information about their smok-ing and drinking history which, in some instances, mayhave occurred more than two decades before the study.Inaccurate reporting of smoking and alcohol consumptionmay have occurred in affected individuals. Because ques-
tionnaires were received from 87 of a potential 153families, the study is subject to bias of ascertainment,because those probands who could not be contacted maybe heavy drinkers and smokers. Because Leber hereditaryoptic neuropathy is a rare disease, these types of bias insuch a study may be difficult to overcome.
Genetic and epigenetic determinants likely influencethe development of vision loss in individuals harboringLeber hereditary optic neuropathy mitochondrial DNAmutations. Retrospective analysis of Leber hereditary opticneuropathy sibships, however, has failed to demonstrate asignificant deleterious association between tobacco or al-cohol consumption and vision loss among individuals atrisk.
ACKNOWLEDGMENTS
We are grateful to the following individuals who referredpatients for participation in the study: M.D. Acierno, MD,Jackson, MS; R.E. Appen, MD, Madison, WI; A.C. Ar-nold, MD, Los Angeles, CA; S.C. Benes, MD, Colombus,OH; P.R. Bringewald, MD, Dallas, TX; M.C. Brodsky,MD, Little Rock, AR; J.C. Calkwood, MD, New Orleans,LA; R. Clark, MD, Johnson City, TN; B.E. Cohan, MD,Ann Arbor, MI; N.G. Congdon, MD, MPH, Baltimore,MD; J.J. Corbett, MD, Jackson, MS; W.T. Cornblath, MD,Ann Arbor, MI; M. Drucker, MD, Tampa, FL; J. Goodwin,MD, Chicago, IL; J.R. Haag, MD, Wheaton, IL; S.S.Hayreh, MD, PhD, Iowa City, IA; J.R. Heckenlively, MD,Los Angeles, CA; E.M. Helveston, MD, Indianapolis, IN;B.N. Hyman, MD, Houston, TX; R.W. Ingram, MD,Midland, TX; D.M. Jacobson, MD, Marshfield, WI; A.T.Johnson, MD, PhD, Iowa City, IA; R.H. Kardon, MD,PhD, Iowa City, IA; D. Kaufman, DO, East Lansing, MI;M.C. Kay, MD, Milwaukee, WI; L.B. Kline, MD, Birming-ham, AL; B.J. Kushner, MD, Madison, WI; J.E. Kwedar,MD, Springfield, IL; B.L. Lam, MD, Miami, FL; J.A.Leavitt, MD, PhD, Rochester, MN; R.H. Legge, MD,Omaha, NE; L.A. Levine, MD, PhD, Madison, WI; R.A.Lewis, MD, Houston, TX; T.J. Martin, MD, Winston-
TABLE 7. Subgroup Analysis of the Risk of Vision Loss Relative Cigarette and Alcohol Consumption in 17 Sibships HarboringMitochondrial DNA Mutations at Nucleotide Positions 3460 or 4484 Assessed with Consideration of the Age of Onset of
Smoking or Drinking Relative to the Age of Onset of Drinking or Smoking
Odds Ratio 95% Confidence Interval P Value
Maximum intensity of tobacco consumption , 75th percentile 2.246 0.841–5.996 0.1060
$ 75th percentile 2.172 0.620–7.606 0.2249
Cumulative tobacco consumption , 75th percentile 2.246 0.841–5.996 0.1060
$ 75th percentile 2.172 0.620–7.606 0.2249
Maximum intensity of alcohol consumption , 75th percentile 1.000 0.291–3.434 0.9999
$ 75th percentile 0.749 0.080–6.956 0.7999
Cumulative alcohol consumption , 75th percentile 0.588 0.101–3.405 0.5535
$ 75th percentile 0.841 0.186–3.797 0.8218
Each group is compared to non-consumers of tobacco or alcohol.
LEBER HEREDITARY OPTIC NEUROPATHYVOL. 130, NO. 6 811
Salem, NC; P.K.J. McNussen, MD, Urbana, IL; O. Melen,MD, Chicago, IL; M. Morciniak, MD, Chicago, IL; J.Nichols, MD, Chicago, IL; I. Pearce, MD, Bellflower, CA;W.T. Shults, MD, Portland, OR; M.L. Slavin, MD, NewHyde Park, NY; D. Stewart, MD, Charlotte, NC; S.Strickler, MD, Vienna, WV; T. Sullivan, MD, Sterling, IL;H.S. Thompson, MD, Iowa City, IA; R. Tokar, MD, WallaWalla, WA; J.D. Trobe, MD, Ann Arbor, MI; R.G.Weleber, MD, Portland, OR; R.D. Yee, MD, Indianapolis,IN; R.Young, MD, Indianapolis, IN; B.R. Younge, MD,Rochester, MN; C.F. Zimmerman, MD, Dallas, TX.
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AMERICAN JOURNAL OF OPHTHALMOLOGY812 DECEMBER 2000