Original Article
Genetic Influence on Smoking — A Study of Male Twins
N Engl J Med 1992; 327:829-833September 17, 1992
- Abstract
- Abstract
Background.
The results of twin and family studies suggest that heredity has a small influence on smoking behavior.
Methods.
We conducted a genetic analysis of several aspects of smoking behavior among subjects in the National Academy of Sciences—National Research Council Twin Registry. The registry includes male twins who were born in the United States between 1917 and 1927 and who were members of the armed forces during World War II. Information on smoking history was available for 4775 pairs of twins, who were first surveyed in 1967 through 1969, when they were 40 to 50 years old, and then resurveyed in 1983 through 1985, when they were 56 to 66. Eighty percent of the subjects in this cohort had smoked at some time in their lives, 60 percent were smokers in 1967 through 1969, and 39 percent were smoking in 1983 through 1985. Similarities between twins in smoking habits at base line and at the second follow-up 16 years later were examined. The comparison of concordance for smoking between monozygotic and dizygotic twins was used to assess the relative contribution of familial and genetic factors.
Results.
In the 1967–1969 survey the ratio of observed to expected concordance for smoking was higher among the monozygotic twins than among the dizygotic twins for those who had never smoked (overall rate ratio, 1.38; 95 percent confidence interval, 1.25 to 1.54), for former smokers (overall rate ratio, 1.59; 95 percent confidence interval, 1.35 to 1.85), for current cigarette smokers (overall rate ratio, 1.18; 95 percent confidence interval, 1.11 to 1.26), and for current cigar or pipe smokers (overall rate ratio, 1.60; 95 percent confidence interval, 1.22 to 2.06). The data also suggest genetic influences on quitting smoking. Monozygotic twins were more likely than dizygotic twins to be concordant for quitting smoking (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45).
Conclusions.
In this cohort of adult male twins, there were moderate genetic influences on lifetime smoking practices. (N Engl J Med 1992;327:829–33.)
Media in This Article
Table 1
Smoking Status According to Zygosity on the 1967–1969 and 1983–1985 Questionnaires.*Table 2
Distribution of Current Cigarette Smokers on the 1967–1969 and 1983–1985 Questionnaires, According to Amount Smoked.*Article Activity
- Article
WITH the increased recognition that nicotine is an addictive drug and that the treatment of nicotine addiction requires a knowledge of individual susceptibility to drug use,1 it is apparent that the effect of genotype on various aspects of smoking behavior needs to be examined.2 The possibility that there are important genetically determined differences in people's susceptibility to nicotine is supported by studies1 , 3 , 4 showing clear differences between strains of mice in the physiologic and behavioral effects of nicotine, in the development of tolerance to these effects, and in the regional distribution of the binding of 125I-labeled bungarotoxin to nicotinic receptors.5 , 6 Twin, family, and adoption studies have shown a consistent degree of heritability of cigarette smoking (i.e., the proportion of phenotypic variation attributed to genetic variation), with a mean heritability of smoking of 0.53 (range, 0.28 to 0.84).7 8 9 10
In the past, estimates were made of the heritability of smoking behavior among large cohorts of twins, such as the Swedish and Finnish twin registries,11 12 13 with cross-sectional data. A similar analysis was recently conducted in a population-based registry in the United States10; that study, however, did not address the question of genetic effects on the intensity of smoking or the ability to quit smoking.
To provide estimates of the genetic effects on these aspects of smoking behavior, we studied a nationally representative cohort of male twins, veterans of World War II who were followed from the initial survey in 1967 through 1969 to the most recent evaluation in 1983 through 1985 and for whom detailed smoking histories were available. These longitudinal data on smoking behavior obtained over a 16-year period provided a unique opportunity to investigate the role of genotype in individual changes in smoking behavior in late adulthood.
Methods
Study Subjects
The data analyzed in this study were from two epidemiologic surveys conducted among persons listed in the National Academy of Sciences—National Research Council Twin Registry. The methods used to construct this twin panel have been described elsewhere.14 Briefly, multiple births of white males in the continental United States from 1917 to 1927 were identified by searching birth certificates. We located about 93 percent of all such births estimated from national statistics to have occurred during those years.15 Among them were 15,924 pairs in which both twins had records in the Master Index File of the Department of Veterans Affairs, indicating that both had served in the armed forces. These records yielded information on the physical examination at induction, hospital admissions and outpatient visits during military service, and home addresses for the twins. All members of the registry were screened for entry into the armed forces during World War II. Pairs in which one or both members had childhood diseases, such as diabetes mellitus or essential hypertension, that would render them unfit for military service were not included.
An initial questionnaire was mailed to 27,502 men in 1965 and 1966, and 20,946 (76 percent) replied. Zygosity was determined mainly on the basis of self-reports of the degree of similarity between the two brothers. Later assessments of the accuracy of these reports based on fingerprints, physical characteristics, and blood typing suggested that approximately 95 percent of the determinations were correct.16
A second questionnaire was mailed between 1967 and 1969 in a collaborative study with investigators responsible for the twin registry of the Karolinska Institute in Stockholm.17 The English-language questionnaire was essentially a translation of one used in Sweden and later adopted for the Finnish twin registry.12 , 13 The objective of these surveys was to obtain information on histories of coronary and respiratory disease, tobacco and alcohol consumption, and related social and environmental factors.
This second questionnaire was mailed to a subgroup of 40-to-50-year-old pairs of twins for whom information on zygosity was available. The rate of response was 75 percent; excluding those not reached in the mailing and those found to have died, the rate of response was 84 percent. The respondents to the 1967–1969 epidemiologic survey were mailed a follow-up questionnaire in 1983, 1984, or 1985. Questions about tobacco and alcohol consumption were posed in the same manner as in the 1967–1969 questionnaire. A total of 7120 men, 56 to 66 years old, responded, representing 67 percent of the total sets of twins responding to the 1967–1969 survey.
Definition of Smoking Status
Information on smoking habits was available for 4775 pairs of twins who responded to the 1967–1969 questionnaire and for the 7120 individual respondents, including 1882 pairs of twins, who responded to the 1983–1985 questionnaire. On the basis of self-reported smoking status, the respondents to the 1967–1969 questionnaire were classified into one of the following subgroups: those who had never smoked — subjects who reported that they had smoked fewer than 100 cigarettes in their lives and were not current cigar or pipe smokers in 1967 through 1969; former smokers — those who had smoked regularly in the past but were not smoking regularly at the time of the 1967–1969 survey; current cigarette smokers — those who reported regular cigarette smoking; and current cigar or pipe smokers — those who smoked cigars or a pipe but not cigarettes regularly. In addition, current cigarette smokers were classified according to smoking intensity as light smokers (1 to 10 cigarettes per day), medium smokers (11 to 30 cigarettes per day), or heavy smokers (more than 30 cigarettes per day).
Respondents to the two questionnaires were classified as continuing nonsmokers (those who reported on the 1967–1969 questionnaire that they had never smoked or were former smokers and who also reported on the 1983–1985 questionnaire that they did not smoke), continuing smokers (those who reported smoking cigarettes regularly on the 1967–1969 and 1983–1985 questionnaires), or quitters (those who reported smoking cigarettes on the 1967–1969 questionnaire but reported that they no longer smoked on the 1983–1985 questionnaire).
Statistical Analysis
A pairwise analysis of smoking behavior was carried out by comparing the observed and expected frequencies of current smokers, former smokers, and those who had never smoked in each zygosity group during the period of follow-up. Since monozygotic twins match totally with respect to genetic factors, whereas matching is only 50 percent in dizygotic pairs, a greater similarity among monozygotic twins than among dizygotic twins is considered evidence of genetic influences. For the 1967–1969 questionnaire, the similarities in smoking status in pairs of twins were compared between the monozygotic and dizygotic respondents. The four categories (those who never smoked, former smokers, current cigarette smokers, and current cigar or pipe smokers) resulted in two four-by-four contingency tables, one for monozygotic and the other for dizygotic twins. From these tables, we estimated the ratio of the observed frequency of concordant pairs (for example, both twins were current smokers) to the expected frequency (calculated as the square of the frequency of individual current smokers). This statistic was termed the ratio of observed to expected concordance for smoking. The relation between the concordance ratio in monozygotic twins and that in dizygotic twins was used as a measure of the influence of genetic factors. The presence of genetic effects was indicated by the rejection of the null hypothesis that the concordance ratios in monozygotic and dizygotic twins were equal.18 We tested for familial effects by testing the concordance ratio in dizygotic pairs with a null hypothesis of a concordance ratio of 1. Corresponding 95 percent confidence intervals were calculated for the ratios of observed to expected concordance in each zygosity group and for the overall ratio of concordance in monozygotic twins to concordance in dizygotic twins. Similar analyses were conducted of smoking intensity and of changes in smoking behavior from the 1967–1969 survey to the 1983–1985 survey.
Results
Smoking Characteristics
The prevalence of cigarette smoking at the time of the two questionnaires is shown in Table 1Table 1
Smoking Status According to Zygosity on the 1967–1969 and 1983–1985 Questionnaires.* according to zygosity. Among those who responded to the 1967–1969 questionnaire, 80 percent of the monozygotic twins and 82 percent of the dizygotic twins reported ever having smoked; 52 and 53 percent, respectively, were current cigarette smokers. The prevalence of cigarette smoking in the registry was 10 percent higher than that reported by the Health Interview Survey19 of noninstitutionalized white men in the United States at about the same time. By the time of the 1983–1985 questionnaire, the prevalence of cigarette smoking was 26 percent among the monozygotic twins and 27 percent among the dizygotic twins. These figures represent a rate of quitting of 45 percent among the monozygotic twins and 42 percent among the dizygotic twins.The data in Table 2Table 2
Distribution of Current Cigarette Smokers on the 1967–1969 and 1983–1985 Questionnaires, According to Amount Smoked.* indicate that the proportion of heavy smokers among those who smoked cigarettes in 1983 through 1985 was higher than the corresponding proportion in 1967 through 1969 (37 percent in the monozygotic twins and 37 percent in the dizygotic twins in 1983 through 1985 vs. 26 and 28 percent, respectively, in 1967 through 1969).Similarities in Smoking Status between Twins in 1967 through 1969
Pairwise comparisons of the ratios of observed to expected concordance according to smoking status in 1967 through 1969 are shown in Table 3Table 3
Pairwise Comparisons of Rates of Concordance, According to Smoking Status in 1967 through 1969.*. All the ratios were significantly greater than 1, suggesting significant familial influences. Also, the concordance ratios for the monozygotic twins were significantly greater than the corresponding ratios for the dizygotic twins, indicating possible genetic influences. The differences in the ratios for monozygotic and dizygotic twins were small, however, with the overall rate ratios (the ratio of concordance in the monozygotic twins to concordance in the dizygotic twins) ranging from 1.18 to 1.60. The overall rate ratio was higher for former smokers (1.59) and current cigar or pipe smokers (1.60) than for current cigarette smokers (1.18).The same method of analysis was applied to the amount smoked by current cigarette smokers at the time of the 1967–1969 survey. Table 4Table 4
Pairwise Comparisons of Rates of Concordance, According to Amount Smoked in 1967 through 1969.* summarizes the results of the pairwise comparison of light (1 to 10 cigarettes per day), medium (11 to 30 cigarettes per day), and heavy (>30 cigarettes per day) cigarette smokers in 1967 through 1969. First, the concordance ratios in the dizygotic twins were not significantly greater than 1 in any category of smoking intensity, indicating the absence of familial influence. Second, the concordance ratios in the monozygotic twins were significantly greater than the corresponding ratios in the dizygotic twins only for the light smokers and heavy smokers. The concordance ratio in the monozygotic twins who smoked 11 to 30 cigarettes per day was 1.11 (95 percent confidence interval, 1.00 to 1.23), which was only marginally significant.Similarities between Twins in Quitting
We also conducted a pairwise comparison of twins classified as continuing nonsmokers, continuing smokers, or quitters and calculated the corresponding concordance ratios in the monozygotic and dizygotic pairs. The results of these analyses for subjects who quit during the 16 years between the surveys are summarized in Table 5Table 5
Comparisons of Rates of Concordance in Twins Who Quit Smoking during Follow-up.*. As with former smokers in the 1967–1969 survey, we observed significant familial effects among the quitters. The corresponding concordance ratio for dizygotic twins was 1.23 (95 percent confidence interval, 1.02 to 1.47), similar to the 1.26 ratio for dizygotic twins among former smokers in 1967 through 1969. There was also evidence of a role for genetic factors, since the concordance ratio for monozygotic twins was significantly greater than that for dizygotic twins (overall rate ratio, 1.24; 95 percent confidence interval, 1.06 to 1.45).Discussion
This analysis was conducted in response to a call for more information about the genetic influences on different aspects of smoking behavior, including intensity (e.g., light, moderate, or heavy smoking) and cessation.7 We found that in the middle phases of life, three components of smoking behavior (never having smoked, current smoking, and quitting) were moderately influenced by genetic factors in this cohort. We observed a genetic effect on the maintenance of smoking that was similar in magnitude to previously published estimates in other populations.9 , 10 The excess rate ratios for current smoking in the present study (overall rate ratios, 1.18 in 1967 through 1969 and 1.28 in 1983 through 1985) were similar in magnitude to those in the male twins from the Finnish twin registry (overall rate ratio, 1.23) and the Swedish twin registry (overall rate ratio, 1.40).20
That not smoking has a genetic component in the members of this cohort is especially interesting in view of their opportunity to smoke and their heavy exposure to smoking during military service in World War II. The importance of nonsmokers to the study of nicotine addiction was recognized some time ago, and it has been argued that people who do not become smokers despite strong environmental pressures may have the greatest biologic motivation to avoid smoking.21 Although our findings suggest that not smoking has a strong genetic component, studies are needed to determine whether this observation derives solely from genetic factors or results from an unknown interaction between genes and the environment.
Smoking cessation showed evidence of significant genetic and familial components in both our surveys. That the ability to quit smoking may involve genetic factors emphasizes the complexity of conceptualizing and treating addiction to nicotine. In the future, treatment approaches may seek genetically susceptible people in whom environmental effects can be maximized to improve rates of quitting.
We found that familial factors had no role in the intensity of smoking and that genetic factors may contribute only in light smokers and heavy smokers. For moderate smokers, there was no evidence of either familial or genetic influences. The excess rate ratio for heavy smoking in the present study (overall rate ratio, 1.48) was similar to the ratios for male twins 18 to 47 years old from the Finnish twin registry (overall rate ratio, 1.56) and the Swedish twin registry (overall rate ratio, 1.76).20
We previously found that the heritability of smoking was 52 percent in the National Heart, Lung, and Blood Institute Twin Study cohort9 and 35 percent in the larger National Academy of Sciences—National Research Council sample from which that cohort was drawn.10 We also found characteristic psychological traits in both monozygotic and dizygotic twins who were discordant for the smoking habit.22
It is likely that at least as far as genetic analyses are concerned, smoking should be viewed as a collection of forms of behavior rather than a single habit. Differences in heritability suggest the existence of subclasses of smoking behavior that may have implications for the selection of effective treatments. For example, knowledge of the aspects of smoking behavior in which genetic influence is greatest may help us identify children at risk for smoking by virtue of their parents' smoking behavior. Preventive messages could then be tailored to them. And the knowledge that there are subtypes of smokers may aid in the fine-tuning of targeted, intensive interventions to help people stop smoking.
Supported in part by a contract (4504–9) and a grant (HL 46115–01) from the National Heart, Lung, and Blood Institute.
*Deceased.
We are indebted to Dr. Marcia Ward for her helpful suggestions.
Source Information
From the Health Sciences Program, SRI International, Menlo Park, Calif. (D.C., G.E.S.); the Medical Follow-up Agency, National Academy of Sciences, Washington, D.C. (D.R.); and the National Heart, Lung, and Blood Institute, Bethesda, Md. (R.F.). Address reprint requests to Dr. Carmelli at the Health Sciences Program, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025.
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