Modifiable Risk Factors as Predictors of All-Cause Mortality: The Roles of Genetics and Childhood Environment

Urho M. Kujala1,, Jaakko Kaprio2 and Markku Koskenvuo3

1 Unit for Sports and Exercise Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland.
2 Department of Public Health, University of Helsinki, and Department of Alcohol Research, National Public Health Institute, Helsinki, Finland.
3 Department of Public Health, University of Turku, Turku, Finland.

Received for publication February 1, 2002; accepted for publication June 10, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors studied familial aggregation of mortality risk factors and their association with future deaths in the Finnish Twin Cohort. Cohort members (n = 15,904) aged 24–60 years and healthy at the end of 1981 who had responded to questionnaires in 1975 and 1981 were followed up for death through June 30, 2001. In individual-based analyses, the age- and sex-adjusted risk of death was higher among persons who were not participating in vigorous leisure physical activity in 1975 and 1981 than in those who were (p < 0.001), and risk was increased among smokers (p < 0.001) and heavy users of alcohol (p < 0.001). The study sample included data on both members of 3,551 dizygotic same-sex twin pairs and 1,772 monozygotic same-sex twin pairs. In pairwise analyses of discordant dizygotic pairs, risks of death were increased among co-twins who were not participating in vigorous activity (p = 0.05), co-twins who were smokers (p < 0.001), and co-twins who were heavy alcohol users (p < 0.001). Correspondingly, among monozygotic twin pairs, a difference in risk was seen only for smoking (p = 0.03). The authors conclude that, after adjustment for childhood environment, a low level of leisure physical activity, smoking, and heavy use of alcohol are associated with increased risks of death, but genetic selection may account for some of the association concerning physical activity and heavy use of alcohol.

alcohol drinking; exercise; genes; mortality; risk factors; smoking; twins

Abbreviations: Abbreviations: CI, confidence interval; ICD-8, International Classification of Diseases, Eighth Revision; MET, metabolic equivalent.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Evidence has been accumulating that mortality is increased among smokers (1) and heavy users of alcohol (2) and reduced among persons with high levels of leisure physical activity (3). However, the evidence is mostly based on observational follow-up studies, one limitation of which is the difficulty of controlling for genetic or other selection bias.

Some inherited biologic characteristics may both make it easier for some individuals to achieve high levels of physical activity or fitness and favor them with longevity. Various studies have shown that physical fitness has a genetic component (4). On the basis of different studies, genetic determination of physical activity varies from low to moderately high, the genetic contribution being higher for vigorous activity than for nonvigorous activity (5). There is also evidence suggesting that there are important genetic influences on other potentially modifiable mortality risk factors, such as smoking (6) and use and abuse of alcohol (7). Consequently, the true extent of the effect of physical activity on delaying mortality as compared with other mortality risk factors is difficult to estimate.

The main aim of our study was to investigate whether childhood environment or genetic selection explains some of the association between low mortality and modifiable mortality risk factors seen in observational studies of individuals. In particular, we investigated physical activity, smoking, and heavy use of alcohol. Before conducting our mortality follow-up, we prospectively recorded data on modifiable risk factors twice within a 6-year period (in 1975 and 1981) to increase validity. First, we confirmed the expected associations between the studied risk factors and future mortality in individual-based analyses. Second, we carried out analyses to confirm the existence of a genetic component in the persistence of the health habits, which is a prerequisite for further analyses concerning genetic selection. Finally, we carried out pairwise analyses of mortality risk among dizygotic and monozygotic twin pairs who were discordant for the persistence of specific risk factors to examine whether familial factors, including genetic ones, modulated the relations between risk behaviors and mortality.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study cohort
The Finnish Twin Cohort was compiled from the Central Population Registry of Finland via procedures described elsewhere (8). In brief, the baseline sample comprised all same-sex twin pairs born in Finland before 1958 with both co-twins still alive in 1967. The target group for the present study consisted of cohort subjects who were working in 1981 (including women working at home and students), gave complete questionnaire data on the intensity of their leisure physical activity in 1975 and 1981, and were aged 24–60 years on January 1, 1982 (n = 17,968). We excluded the 2,064 cohort members who had chronic disease (except for hypertension; see criteria below) as of January 1, 1983. The final study cohort comprised 15,904 subjects (7,811 men and 8,093 women) who were apparently healthy at baseline (table 1). Because of disease, death, nonresponse to questionnaires (see details below), and the cohort selection procedure (8), 4,578 (28.8 percent) of the subjects included in the final study cohort did not have a co-twin for the present analysis. Numbers of same-sex twin pairs by zygosity were: 3,551 dizygotic pairs (1,736 male and 1,815 female), 1,772 monozygotic pairs (823 male and 949 female), and 340 pairs (174 male and 166 female) whose zygosity was unknown.


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TABLE 1. Distribution of members of the Finnish Twin Cohort who were healthy and aged 24–60 years at the end of 1981, by sex, age, and zygosity
 
The subjects were mailed similar questionnaires in 1975 and 1981. Among other topics, the questionnaires included items on physical activity, occupation, alcohol use, smoking, and physician-diagnosed diseases. Among subjects whose addresses could be identified (93.5 percent) in 1975, the response rate for twins was 87.6 percent. The re-response rate in 1981 among subjects who had responded in 1975 and were alive in 1981 was 90.7 percent.

Zygosity (monozygotic, dizygotic, or unknown) was defined by means of a validated questionnaire method that has been used in other large twin studies (9). The twofold ratio of dizygotic twins to monozygotic twins reflects the high frequency of dizygotic twinning that existed in Finland until the 1960s (10).

Because chronic disease may restrict a person’s ability to exercise and may change a person’s smoking and drinking habits, we excluded at baseline subjects with certain chronic diseases. On the basis of the 1981 questionnaire, we excluded subjects who reported physician-diagnosed angina pectoris, myocardial infarction, or diabetes mellitus or who had angina pectoris according to standard chest-pain history items included in the questionnaire (11, 12). Using the nationwide hospital discharge register (13), which is considered reliable, we also excluded subjects who had had an inpatient admission for diabetes (International Classification of Diseases, Eighth Revision (ICD-8) (14), code 250), cardiovascular disease other than hypertension or venous diseases (ICD-8 codes 390–399 and 410–449), or chronic obstructive pulmonary disease (ICD-8 codes 490–493) between 1972 and December 31, 1982. In addition, we excluded all subjects who had been granted reimbursable medication for selected chronic diseases other than hypertension before January 1, 1983, on the basis of data obtained from the Social Insurance Institution of Finland (15). Finally, we excluded subjects who had had incident malignant cancer before 1983 according to the Finnish Cancer Registry (16).

Risk factor assessment
We used data on mortality risk factors (health habits) based on responses to questions that had been asked similarly in the 1975 and 1981 questionnaires. We used data that we considered valid on the basis of earlier studies (15, 1720). We asked about health habits prospectively two times to increase the validity of data on predictors of death. Subjects whose health habits were similar in 1975 and 1981 were regarded as having a persistent level of a given health habit. To obtain a sufficient number of observations by category in our analyses, we dichotomized data on each risk factor. Subjects with missing data for some questions (0–6.5 percent of subjects) were excluded from specific analyses. The numbers of subjects with complete data on each health habit are given in table 2.


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TABLE 2. Health habits in 1975 and 1981 and mortality from 1982 to June 30, 2001, among members of the Finnish Twin Cohort (n = 15,904) who were healthy and aged 24–60 years at the end of 1981
 
Assessment of participation in vigorous physical activity was based on the following question: "Is your physical activity during leisure time about as strenuous, on average, as: 1) walking, 2) alternately walking and jogging, 3) jogging (light running), or 4) running?" Those who chose alternative 2, 3, or 4 were classified as participating in vigorous activity.

Assessment of leisure activity volume in the form of a metabolic equivalent (MET) index was based on a series of structured questions (questionnaire available from the authors) (17, 18) on leisure physical activity (monthly frequency, mean duration, and mean intensity of physical activity sessions) and physical activity during the journey to and from work. We calculated the activity MET index by assigning a multiple of resting metabolic rate (MET score) to each activity and by calculating intensity x duration x frequency of activity (18). The activity MET index was expressed as the summary score of leisure MET-hours per day. Subjects whose volume of activity was >=2 MET-hours/day (corresponding to approximately 30 minutes of walking per day) were classified as physically active at leisure.

The age- and sex-adjusted mean leisure MET index in 1981 for persons who participated in vigorous activity in 1975 and in 1981 was 4.51 (standard error = 0.04) MET-hours/day, as compared with 1.65 (standard error = 0.04) MET-hours/day for persons who did not (p < 0.001). The age- and sex-adjusted mean leisure MET index in 1981 for persons whose leisure MET index was >=2 in both 1975 and 1981 was 5.56 (standard error = 0.04) MET-hours/day, and for those whose MET index was <2 in 1975 and 1981, it was 0.92 (standard error = 0.04) MET-hours/day (p < 0.001). The relations for men and women were very similar.

Assessment of work-related physical activity was based on responses to the question, "What kind of work did/do you do (current work, or work you last did)?," with four possible responses: 1) "mainly sedentary work, which requires very little physical activity," 2) "work which involves standing and walking but no other physical activity," 3) "work which in addition to standing and walking requires lifting and carrying," and 4) "heavy physical work." Those who chose the first alternative were classified as having sedentary work.

Smoking status was classified from responses to a detailed smoking history questionnaire including questions on quantity smoked and ages at initiation and cessation (19). Subjects who reported smoking regularly (i.e., current smokers who smoked daily or almost daily, with a lifetime quantity of at least 5–10 packs of cigarettes) at the time of administration of the questionnaire were classified as smokers.

The dichotomous index of heavy use of alcohol was obtained from a drinking density item that asked whether "at least once a month and on a single occasion" the respondent consumed more than five beers, a bottle of wine, or a half-bottle of spirits (20). In addition, alcohol use was recorded in beverage-type-specific items on frequency and quantity, converted into grams of absolute alcohol per day (20).

Mortality follow-up and statistical analyses
Follow-up for all-cause mortality began on January 1, 1982, and continued through June 30, 2001. During follow-up, dates of death were available from the Population Register Centre of Finland (updated in August 2001).

There were 303,476 person-years of follow-up in total. We first studied all-cause mortality in the entire study cohort (n = 15,904 individuals) by calculating hazard ratios during follow-up according to different persistent health habits or changes in health habits using Cox’s proportional hazards model. Because the data on individuals were from twins, the clusters of correlated observations (twin pairs) were taken into account in computing standard errors of the coefficients. We then adjusted the results on physical activity variables for smoking and heavy alcohol use.

Pairs of co-twins represent persons who have nearly always shared the same childhood environment and have some (dizygotic) or all (monozygotic) of their genes in common by descent. When the intrapair correlation concerning a specific risk factor is higher among monozygotic (MZ) twin pairs than among dizygotic (DZ) pairs, genetic influences are inferred to be present. Familial aggregation of different risk factors was studied by first calculating polychoric intraclass correlations (r) for monozygotic and dizygotic pairs and then the proportion of variance attributed to additive genetic effects (i.e., the fraction of population variance due to genetic variance = 2[rMZrDZ]), under the basic assumptions of the classical twin study (21). Numbers of twin pairs who had complete data for each calculation are shown in table 3.


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TABLE 3. Familial aggregation of mortality risk factors among same-sex twin pairs in the Finnish Twin Cohort, 1975 and 1981
 
Table 4 summarizes theoretical interpretations of analyses on individuals and twin pairs when familial and genetic selection bias are being investigated. Twin pairs discordant for death and for specific risk factors were examined to determine whether twin members whose health habits differed from those of their sex- and age-matched co-twins had a different risk of death. Quantity of leisure physical activity and use of alcohol among twin pairs persistently discordant for these health habits were calculated, and differences were tested by paired t test (table 5). The twins were classified as discordant for death if only one had died during follow-up. Numbers of twin pairs persistently discordant for each health habit and death are shown in table 6. We calculated odds ratios for death differently in all discordant twin pairs (including pairs with unknown zygosity), dizygotic discordant twin pairs, and monozygotic discordant twin pairs for each risk factor and tested the results for significance by McNemar’s test. Because smoking was also seen to be a strong mortality risk factor on the basis of pairwise analysis among monozygotic twin pairs, we adjusted other results for smoking by conditional logistic regression. We also tested the homogeneity of odds ratios by zygosity.


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TABLE 4. Theoretical interpretation of findings on discordant twin pairs in investigations of the roles of genetic and other familial factors in associations between risk factors and mortality*
 

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TABLE 5. Leisure metabolic equivalent index in 1981 among twin pairs in the Finnish Twin Cohort who were persistently discordant for leisure physical activity in 1975 and 1981 and use of alcohol in 1981 among twin pairs persistently discordant for heavy alcohol use in 1975 and 1981
 

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TABLE 6. Mortality among 5,663 twin pairs discordant for persistent health habits in 1975 and 1981 in the Finnish Twin Cohort, 1982–June 30, 2001
 
Data were analyzed with SAS software (version 6.12; SAS Institute, Cary, North Carolina) and Stata software (release 7.0; Stata Corporation, College Station, Texas) (22). All significance tests were two-tailed.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Individual-based analyses of mortality risk
During follow-up, 945 (645 men and 300 women) of the 15,904 subjects who had been healthy at baseline died. The associations between health habits in 1975 and 1981 and deaths occurring between 1982 and June 30, 2001, are shown in table 2. There was no difference in mortality by zygosity (the age- and sex-adjusted hazard ratio for monozygotic twins compared with dizygotic twins was 0.99 (95 percent confidence interval (CI): 0.85, 1.14)). After adjustment for age and sex, subjects who did not participate in vigorous physical activity in 1975 or 1981 had a higher hazard of death (hazard ratio = 1.89, 95 percent CI: 1.60, 2.24) than those who were participating (table 2). This finding persisted after further adjustment for smoking (hazard ratio = 1.62 (95 percent CI: 1.36, 1.92), p < 0.001) and heavy alcohol use (hazard ratio = 1.65 (95 percent CI: 1.38, 1.96), p < 0.001). After adjustment for age, sex, and smoking, the mortality hazard ratio for participants whose leisure MET index was lower than 2 MET-hours/day in 1975 and 1981 was 1.19 (95 percent CI: 0.96, 1.48) in comparison with those whose MET index was >=2 MET-hours/day (p = 0.11). Persistent smoking was associated with a greatly increased risk of death (hazard ratio = 2.81, 95 percent CI: 2.44, 3.23)), as was persistent heavy alcohol use (hazard ratio = 2.48, 95 percent CI: 2.11, 2.92).

Familial aggregation of risk factors
There were 5,663 same-sex twin pairs in the cohort (2,733 male pairs and 2,930 female pairs; 1,772 monozygotic, 3,551 dizygotic, and 340 pairs with unknown zygosity). Table 3 shows the polychoric correlations of different risk factors among dizygotic and monozygotic twin pairs, as well as the proportions of variance attributed to additive genetic effects. The polychoric correlations were lower for physical activity volume than for participation in vigorous activity. The proportion of variance attributed to additive genetic effects was at least 30 percent for all studied risk factors and was highest for vigorous physical activity (55 percent).

Pairwise analysis of mortality risk
Among the twin pairs, there were 706 same-sex twin pairs that were persistently discordant for participation in vigorous leisure physical activity. Their pairwise difference in leisure MET index is shown in table 5. The pairwise odds ratios of death according to different risk factors are shown in table 6. Among pairs discordant for participation in vigorous physical activity, there were 68 pairs also discordant for death during follow-up (table 6). Among these pairs, in dizygotic pairs the risk of death was higher in the inactive member than the active co-twin (odds ratio = 1.82, p = 0.05), but this association was not seen among monozygotic pairs (odds ratio = 1.00, p = 1.00). These findings persisted after adjustment for smoking. Among twin pairs discordant for leisure physical activity volume, there was a tendency toward pairwise difference in risk among dizygotic pairs (odds ratio = 1.86, p = 0.06), but again we were unable to see this among monozygotic pairs. Sedentary workers had lower risk than nonsedentary workers in all analyses. The risk of death among smoking twins compared with their nonsmoking co-twins differed among both dizygotic pairs (odds ratio = 3.33, p < 0.001) and monozygotic pairs (odds ratio = 5.50, p = 0.03). Increased risk of death was seen in dizygotic twins who used alcohol heavily as compared with their co-twins not using it heavily (odds ratio = 4.88, p < 0.001), but this was not the case among monozygotic pairs, and these findings persisted after adjustment for smoking. The difference in the pairwise odds ratios for death between dizygotic and monozygotic twins was statistically significant for heavy use of alcohol (heterogeneity test: p = 0.007) and was marginally significant for leisure physical activity volume (p = 0.05).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this paper, we report the results of concordance and mortality analysis carried out among members of the Finnish Twin Cohort who were assessed for lifestyle behaviors in 1975 and 1981 and then followed for mortality from 1982 to June 30, 2001. We first conducted mortality analyses by treating all cohort members as individuals. These analyses gave us expected findings consistent with the large amount of literature indicating increased mortality among smokers (1) and heavy users of alcohol (2) and reduced mortality among subjects participating in vigorous leisure physical activity (3).

Heritability analyses revealed different proportions of additive genetic effects for the various behaviors consistent with evidence from prior research on families, twins, and adoptees (57). When a behavior is associated with mortality and adopting the behavior is influenced by genes, genetic factors may or may not confound the association between the behavior and mortality.

To examine the possible existence of genetic and other familial selection bias in individual-based analyses, we carried out pairwise mortality analyses among dizygotic and monozygotic twin pairs discordant for various lifestyle behaviors (table 6). Comparison of persistently discordant twin pairs for the various behaviors revealed different patterns of evidence in favor of excess mortality among members of discordant pairs with the unhealthy "high risk" behavior as compared with the co-twin with the healthy "low risk" version of the behavior. This means differing interpretations of the findings concerning different behaviors (table 4). In agreement with earlier data on twins (23, 24), smoking was associated with excess mortality among both dizygotic and monozygotic twin pairs, which implies and confirms the strong causal association between smoking and increased risk of death. Concerning heavy use of alcohol and physical activity, a pairwise mortality difference could be seen among dizygotic twin pairs discordant for the health habit. This would imply that early family environment cannot account for the difference. Of our twins, 91.5 percent had lived together at home until they reached the age of 16 years. However, concerning physical activity and heavy use of alcohol, a pairwise mortality difference could not be demonstrated among monozygotic pairs discordant for these health habits, despite a clear difference in intrapair mean physical activity MET index and mean consumption of alcohol (table 5). Despite the modest statistical power of our analyses among monozygotic pairs, it seems that genetic factors may account for some of the associations between mortality and physical activity as well as between mortality and heavy use of alcohol. The lower prevalence of persistent discordances of monozygotic twin pairs compared with dizygotic twin pairs concerning heavy use of alcohol (6.1 percent vs. 10.8 percent) and participation in vigorous leisure physical activity (8.9 percent vs. 14.6 percent) decreases the statistical power of pairwise analyses on the one hand but supports the existence of genetic selection on the other hand.

The pairwise odds ratios for death between heavy and nonheavy users of alcohol differed by zygosity. To our knowledge, no other studies have investigated heavy use of alcohol and risk of death among monozygotic and dizygotic twin pairs, though Carmelli et al. (25) evaluated abstinence-discordant pairs and mortality. Since there is accumulating evidence for genetic effects on alcohol use and alcoholism (7, 20, 26), our finding suggests that some of the relation between heavy alcohol use and mortality is due to genetic selection. Evidently, some people are genetically more prone to heavy alcohol use and related increased risk of death. Biologic and other factors making individuals prone to heavy alcohol use or binge drinking should be studied in more detail.

In our study, the association between a high volume of leisure activity and low mortality was weaker than that between vigorous activity and low mortality, again in accordance with earlier studies (3). There may be numerous social, psychological, and biologic determinants of the ability to exercise vigorously or to increase one’s physical activity level in adulthood. Because we saw no pairwise difference in the mortality risk of monozygotic twin pairs who were persistently discordant for leisure physical activity, we must consider that some of the determinants of physical activity may also be predictors of future mortality risk. Inherited characteristics of people who find it difficult to exercise should be compared in more detail with those of people who participate in vigorous activity. One example of how genetic selection may play a role here and one candidate for investigation is the properties of skeletal muscle (2729), because having a high inherited percentage of slow twitch muscle fibers has been associated with high-endurance fitness, high oxidative capacity, high insulin sensitivity, high levels of high density lipoprotein cholesterol, and low risk of obesity (28, 29). We have observed that both an aptitude for endurance athletic events and later vigorous physical activity independently predict low incidence of coronary heart disease (29). Because there are no randomized clinical trials showing that physical activity reduces mortality (3), different types of scientific studies are still needed to determine the overall health benefits of physical activity. When tailoring clinical physical activity interventions, we must remember that not all individuals are suited to the same guidelines for exercise intensity, because the ability to exercise seems to vary not only by training background but also by genetic predisposition. Preventive programs focusing on both an increase in physical activity and smoking cessation might be considered.

Manual workers had similarly higher risks of death than sedentary workers in all analyses, which undermines the case for a strong causal biologic link between high physical activity and low mortality. The results of many recent studies (though not all) agree with ours (3032). To investigate which factors explain the decreased mortality of persistently sedentary workers compared with manual workers in our cohort, we adjusted this finding for income level and schooling, which changed the hazard ratio from 0.66 to 0.76 (95 percent CI: 0.63, 0.91). Further adjustment for smoking, heavy use of alcohol, and participation in vigorous leisure physical activity changed the hazard ratio to 0.79 (95 percent CI: 0.66, 0.96). Thus, many factors seem to contribute to the difference in mortality risk between manual and sedentary workers.

Although our twin cohort was based on the Finnish adult population, which comprises 2,051,000 persons (8), our statistical power to carry out pairwise comparisons among monozygotic twin pairs discordant for persistent health habits was relatively low. Therefore, when ignoring other analyses and focusing on the pairwise mortality analyses among twin pairs discordant for physical activity, another interpretation might be that the effects are the same in monozygotic and dizygotic pairs and the results in the monozygotic pairs were nonsignificant because of an insufficient number of deaths. We also had to dichotomize our recorded risk factor data, which somewhat compromised validity. The limitations of twin studies include the fact that monozygotic twins may be discordant for certain risk factors for reasons other than those prevailing between two unrelated individuals in the general population (33). Discordances may also last for a shorter time in monozygotic pairs (33); but to overcome that, in the present study we recorded discordance prospectively at two different time points 6 years apart.

In conclusion, in comparison with the causal link between smoking and future mortality, the associations between physical activity and mortality as well as between alcohol use and mortality are more complex. To avoid overestimating the expected benefits of physical activity on mortality, the results of observational follow-up studies, in view of the lack of data from prospective randomized trials (3), should be interpreted with caution. Our results stress the importance of reducing smoking to prevent premature deaths. Despite our results pointing to a possible role of genetic selection, a physically active lifestyle may bestow an improved quality of life and other health benefits. Reducing heavy use of alcohol is also important, not least for social well-being and mental health.


    ACKNOWLEDGMENTS
 
This study was supported by the Academy of Finland and the Finnish Ministry of Education.


    NOTES
 
Correspondence to Dr. Urho Kujala, Unit for Sports and Exercise Medicine, Mannerheimintie 17, FIN-00250 Helsinki, Finland (e-mail: Urho.Kujala{at}helsinki.fi). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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