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American Journal of Epidemiology Advance Access originally published online on April 7, 2008
American Journal of Epidemiology 2008 167(11):1342-1348; doi:10.1093/aje/kwn061
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Toenail Nicotine Levels as Predictors of Coronary Heart Disease among Women

Wael K. Al-Delaimy1, Meir J. Stampfer2,3,4, JoAnn E. Manson2,3,5 and Walter C. Willett2,3,4

1 Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, CA
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA
3 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
4 Department of Nutrition, Harvard School of Public Health, Boston, MA
5 Division of Preventive Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA

Correspondence to Dr. Wael K. Al-Delaimy, 3855 Health Sciences Drive, #0901, La Jolla, CA 92093 (e-mail: wael{at}ucsd.edu).

Received for publication November 2, 2007. Accepted for publication February 26, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors assess the ability of toenail nicotine levels as a biomarker to predict incident coronary heart disease (CHD). A nested case-control study was carried out among 62,641 women aged 36–61 years in the Nurses' Health Study cohort who provided toenail clippings in 1982. Between 1984 and 1998, 905 incident CHD cases were diagnosed and matched with two controls by age and date of toenail collection. Using multivariate logistic regression analyses, the authors found a statistically significant dose-response association between increasing toenail nicotine levels and risk of CHD (ptrend < 0.0001); women in the highest quintile had a relative risk of 3.44 (95% confidence interval (CI): 2.56, 4.62) compared with women in the lowest quintile. With each increase in the log-transformed unit of continuous toenail nicotine levels, there was a 42% increase in the risk of CHD (relative risk = 1.42, 95% CI: 1.33, 1.52). The association remained significant when the number of cigarettes smoked and passive smoking were included as covariates (relative risk = 1.12, 95% CI: 1.01, 1.24). In conclusion, toenail nicotine levels are predictive of CHD among women independent of other risk factors and remained significant even after adjustment for history of cigarette smoking.

biological markers; cohort studies; coronary disease; nails; nicotine; tobacco

Abbreviations: CHD, coronary heart disease; CI, confidence interval; RR, relative risk


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Exposure to tobacco smoke has been associated with many illnesses among children and adults (1). Many cohort studies have found an increased coronary heart disease (CHD) risk among passive and active smokers (2–4). There is some inconsistency between cohort studies in the magnitude of association between active or passive smoking and risk of incident CHD, but the relative risks derived from meta-analyses studies are estimated to be 2.5 for smokers and 1.21 for passive smokers (4, 5). Most previous studies relied only on questionnaire measures of exposure, which are subject to inaccuracies. Even among active smokers, no study has attempted to assess the additional effects of passive smoking or the impacts of smoking habits, such as puff length and frequency, that greatly influence the dose of tobacco smoke exposure for the same number of cigarettes smoked (6–9).

Tobacco smoke may increase the risk of CHD through mechanisms that can involve increased platelet aggregation, damage to the arterial endothelium, coronary spasm, reduced high density lipoprotein cholesterol, and oxidative stress (10, 11). Although higher levels of carbon monoxide and other factors may contribute to the effects of smoking on risk of CHD, nicotine is also thought to play a major role in these mechanisms (12). Therefore, there is no doubt that tobacco smoking is a cause of CHD, but imperfect measurement of the total components of exposure has likely led to poor understanding of the true magnitude of CHD risk.

Biomarkers offer an objective complement to self-reports of tobacco exposure. Many biomarkers of exposure to tobacco have been used in the past, including carbon monoxide (13), cotinine in body fluids (14–18), 4-aminobiphenyl hemoglobin adducts (19, 20), and other biomarkers (21). The main disadvantage of these biomarkers is their inability to reflect long-term exposure to tobacco smoke exposure and, in the case of 4-aminobiphenyl, they are expensive and nonspecific. The widely used urine cotinine biomarker usually measures only 1–3 days of past exposure and thus has poor within- and between-individual reliability because of day-to-day variability of overall tobacco exposure (16, 22, 23), and there are logistic difficulties in collection and storage of urine samples, especially in large epidemiologic studies.

Toenail nicotine level has been shown to be a promising new biomarker for differentiating individuals on the basis of their reported exposure to tobacco (24). Because toenails grow slowly at a rate of 1 cm every 9–12 months (25), toenail nicotine levels offer the most time-integrated objective measure of exposure to tobacco smoke among currently available biomarkers. Reported smoking exposure explained only approximately 60 percent of the variability of toenail nicotine levels (26), suggesting that these measures may reflect different aspects of smoking exposure. Objective data are typically more effective than subjective statements about risks when attempting to motivate individuals to make difficult changes such as quitting smoking. Therefore, this method may prove particularly useful in clinical settings where physicians and other health-care professionals advise patients to quit smoking. We therefore aimed to investigate the ability of toenail nicotine levels, representing the overall burden of exposure to tobacco smoke, to predict CHD among women participating in the Nurses' Health Study. We also assessed whether this biomarker independently adds to the risk of CHD over and above reported exposure to tobacco smoke.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The Nurses' Health Study was established in 1976, when 121,700 US female registered nurses aged 30–55 years and residing in one of 11 states completed a mailed questionnaire regarding medical history and lifestyle factors. This information has been updated every 2 years from 1976. Cardiovascular risk factors, such as smoking, history of diabetes, hypertension, high cholesterol, and dietary variables, have been updated regularly. In 1982, all participants were asked to collect toenail clippings from their 10 toes and to send them in the provided envelope.

Study design
A nested case-control study was carried out to assess the ability of nicotine to predict incident cases of CHD in a dose-response relation among the 62,641 women who provided toenail clippings in 1982 and were free of cancer, heart disease, and stroke in 1982. Incident CHD cases (nonfatal myocardial infarction, fatal coronary heart disease) diagnosed after returning the nails in 1982 but before the June 1, 1998, questionnaire were matched to two controls. Women with CHD diagnosed before nail collection in 1982 were excluded. In addition, women with reported stroke, angina, or coronary artery bypass surgery before nail return were excluded to avoid bias related to changes in smoking habits resulting from such diagnosis. Women diagnosed with cancer at baseline, other than nonmelanoma skin cancer, were also excluded from the analyses. Two controls were randomly selected for each case, matched on age and time of nail collection, from the pool of women who remained free of CHD.

Smoking history
At the beginning of the Nurses' Health Study cohort in 1976, participants were asked at what age they started smoking and at what age they stopped if they were not smoking. If they were active smokers, they were asked how many cigarettes they smoked per day. The smoking status question was repeated in each 2-year cycle including 1982. Passive smoking was recorded only in the 1982 questionnaire.

For exposure assessment of active smokers, those who reported being current smokers in the 1982 questionnaires were considered as active smokers. Passive smokers were those who reported exposure to tobacco smoke from the home or work environment in the 1982 questionnaire and were never smokers in the 1982 questionnaire. Never exposed are those who were never smokers up to the 1982 questionnaire and reported not being exposed to tobacco smoke from others in 1982. Past smokers are those who reported being smokers previously but were not active smokers in 1982.

Ascertainment of CHD endpoints
On each questionnaire, participants indicated whether they had been diagnosed with any major medical condition, including heart disease. The diagnosis of CHD in our analysis was incident CHD (including nonfatal myocardial infarction and fatal CHD). Women who reported a nonfatal myocardial infarction were asked permission to review their medical records, which were used to confirm the diagnosis according to the World Health Organization diagnostic criteria (i.e., symptoms plus either cardiac enzyme level elevations or diagnostic electrocardiographic changes). Physicians blinded to exposure status conducted the record reviews. Only confirmed nonfatal myocardial infarction cases were included in the analyses.

Fatal CHD cases were ascertained by reviewing the state vital records and by searching the National Death Index. This search was supplemented by reports from next of kin, and their written permission was sought to review the medical records. Fatal CHD was defined as fatal myocardial infarction if confirmed by hospital records or by autopsy or as CHD death when recorded on the death certificate (if this was the underlying and most plausible cause and if there was previous evidence of CHD). We designated as presumed fatal CHD those cases in which CHD was the underlying cause on the death certificate but no records were available. Also included under fatal CHD were cases of sudden death (within 1 hour of onset of symptoms) with no plausible explanation other than coronary disease. All CHD cases were included in the analyses (n = 905) if they were diagnosed after the return of toenails in 1982 but before June 1, 1998.

Toenail nicotine assay
Analysis of toenails was carried out at the Wellington Hospital (New Zealand) biochemistry laboratory by use of high-performance liquid chromatography with electrochemical detection (27), a method developed and used for analysis of hair and nail nicotine levels. This laboratory assay has been validated by comparing it with other biomarkers and reported history of tobacco exposure (28, 29). The within-batch coefficient of variation for duplicates in this study was 12.6 percent. Cases and controls were submitted to the laboratory as matched sets but in random order with the laboratory blinded as to case-control and smoking status. To reduce random error, we ran all samples in duplicates when there was enough toenail weight. Only 13.3 percent of the toenail samples were run in singlicate because of insufficient toenail weight.

Data analyses
The toenail nicotine levels and other covariates were not normally distributed, and we therefore used the nonparametric Wilcoxon rank sum test to assess the difference in nicotine levels between CHD and their controls. The chi-square test was used to assess categorical variables in relation to CHD status. We used the PHREG procedure in SAS software (SAS Institute, Inc., Cary, North Carolina) for conditional logistic regression analyses for matched analyses to model the independent predictors of CHD.

Toenail nicotine levels were initially analyzed as quintiles by use of indicator variables with the lowest quintile as the referent group. We adjusted for the following CHD risk factors at the time of toenail collection: body mass index (kg/m2), physical activity (<1, 1–1.9, 2–3.9, 4–6.9, and ≥7 hours per week of moderate to vigorous activity), history of high cholesterol (yes no), history of high blood pressure (yes, no), history of diabetes (yes, no), parental history of myocardial infarction before the age of 60 years (yes, no), use of postmenopausal hormone replacement therapy (premenopausal status, never used, current use, or past use), and aspirin intake (yes, no). Alcohol use (0, 0.1–4.9, 5–14.9, and 15 g/day) was recorded only in 1980 (2 years before toenail collection) but was included in the model on the assumption that women did not change their drinking habits during these 2 years. The state of residence did not influence the association between exposure to tobacco and CHD and was therefore not included in the analyses. We then modeled the nicotine level as a continuous log-transformed variable for the rest of our analyses. We repeated the above model for continuous nicotine levels separately among active smokers. We also carried out the analyses for fatal CHD and nonfatal myocardial infarction separately.

We used unconditional logistic regression analyses (PROC LOGISTIC; SAS Institute, Inc.), adjusting for age and date of toenail return, to conduct stratified analyses of the association between nicotine levels and CHD, also including continuous variables for alcohol intake, physical activity, and body mass index unless they were the stratifying variable. The relatively small number of women in some of these strata limited our ability to carry out matched analyses or to include all covariates in all models.

We also assessed the independent association of toenail nicotine levels with CHD apart from the risk predicted by reported smoking by including in the model the current number of cigarettes smoked in 1982, which was the strongest predictor of toenail nicotine levels (26) and risk of CHD. For all the variables of interest, we calculated the 95 percent confidence intervals. All p values are two sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
The age-adjusted characteristics of women in 1982 according to quintiles of toenail nicotine are presented in table 1. There was no difference in age, body mass index, aspirin use, or history of high cholesterol according to the toenail nicotine levels. Women in the highest toenail quintiles were physically less active, had a lower body mass index, drank a higher amount of alcohol, and were more likely to have histories of high blood pressure, diabetes, and family history of myocardial infarction than women in the lower quintiles.


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  		TABLE 1. Age-adjusted characteristics of women in the Nurses' Health Study according to quintiles of toenail nicotine levels in 1982

 
The distributions of the baseline CHD risk factors according to cases of CHD and controls are presented in table 2. The mean nicotine levels for cases were twofold higher than the mean nicotine levels for controls. As expected, cases had a significantly higher body mass index, a lower intake of alcohol, and less physical activity, and they were more likely to be current smokers. Cases also reported a higher prevalence of elevated cholesterol, high blood pressure, and a family history of myocardial infarction compared with controls. Age, aspirin use, and current use of postmenopausal hormone replacement therapy were not different between the cases and the controls.


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  		TABLE 2. The distribution of CHD* risk factors at baseline in 1982 between cases and controls in the Nurses' Health Study during follow-up until 1998{dagger}

 
In the age-matched analysis, there was a statistically significant positive dose-response association between toenail nicotine levels and risk of CHD (ptrend < 0.0001). The relative risk for the highest compared with the lowest quintiles of toenail nicotine levels in the age-matched analyses was 3.26 (95 percent confidence interval (CI): 2.48, 4.27). As shown in figure 1, after adjustment for other risk factors for CHD, the highest quintile had a relative risk of 3.44 (95 percent CI: 2.56, 4.62) compared with the lowest quintile.


Figure 1
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  		FIGURE 1. The relative risk (RR) and 95% confidence intervals of coronary heart disease (CHD) among women in the Nurses' Health Study between 1982 and 1998 according to quintiles of toenail nicotine levels in 1982 adjusted for other CHD risk factors in multivariate analyses. The model included the CHD risk factors of alcohol intake, physical activity, family history of myocardial infarction, aspirin use, postmenopausal hormone use, body mass index, history of cholesterol, history of diabetes, and history of hypertension.

 
We also assessed continuous log-transformed nicotine levels in univariate analyses for the matched cases and controls. With each increase in the log-transformed unit of toenail nicotine levels matched for age and date of nail return, there was a 40 percent increase in the risk of CHD (relative risk (RR) = 1.40, 95 percent CI: 1.31, 1.48). This was slightly increased when other CHD risk factors were included in the model (RR = 1.42, 95 percent CI: 1.33, 1.52).

When analyses were limited to current smokers (n = 777), the risk was similar (RR = 1.40, 95 percent CI: 1.09, 1.81). In separate analyses for fatal CHD and nonfatal myocardial infarction, there was no appreciable difference in the relative risk; the relative risk for fatal CHD was 1.40 (95 percent CI: 1.22, 1.62), while it was 1.43 (95 percent CI: 1.32, 1.55) for nonfatal myocardial infarction.

We then carried out analyses stratified by smoking status, history of high blood pressure, diabetes, current use of postmenopausal hormones, family history of myocardial infarction, aspirin use, history of high cholesterol, body mass index (<25, ≥25), alcohol use (0–4.9 g/day, ≥5 g/day), and physical activity (<3.5 hours/week or ≥3.5 hours/week) (table 3). We found no significant association between nicotine levels and CHD among never exposed nonsmokers, passive smokers, and past smokers, but the risk among current smokers was significantly increased (pinteraction = 0.003). None of the interactions between smoking and the other stratifying variables was significant. However, in general, the magnitude of association of toenail nicotine level (log transformed) was higher in the stratum of the variable representing women without the CHD risk factor, such as those with no history of cholesterol, no history of high blood pressure, no history of diabetes, or no family history of myocardial infarction.


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  		TABLE 3. Stratified analyses of the association between log-transformed, continuous toenail nicotine levels (ng/mg) and risk of CHD* according to selected CHD risk factors, Nurses' Health Study, 1982–1998

 
We also assessed the independent prediction of CHD risk with tobacco exposure measured by toenail nicotine levels beyond reported exposure to tobacco smoke. Therefore, we included in the multivariate analyses the variable for the categories of the number of cigarettes smoked per day at baseline in 1982 and reported passive smoking, in addition to log-transformed nicotine levels. Independent of reported cigarette smoking and reported passive smoking, the association between toenail nicotine level and risk of CHD was attenuated but was still significant (RR = 1.12, 95 percent CI: 1.01, 1.24). In this model, the relative risk for each increase in the category of cigarettes smoked per day was 1.33 (95 percent CI: 1.22, 1.46). The –2 log likelihood for the logistic regression model with all variables (including log nicotine) was 1,431.0 and, for the model without log nicotine, was 1,435.4 (Wald p < 0.0001), indicating that toenail nicotine is predicting CHD risk significantly beyond that from reported smoking and the other covariates.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
To our knowledge, our study is the first to show that toenail nicotine level as a biomarker of overall burden of tobacco smoke exposure is strongly predictive of CHD among women independent of other risk factors. This association was consistent when using both categorical and continuous variables for toenail nicotine levels.

Although the continuous measures of toenail nicotine and reported smoking cannot be compared directly because of their different scales, our relative risks and 95 percent confidence intervals for CHD using toenail nicotine levels are comparable to those from reported smoking. The relative risk for women in the highest category of active smokers (those who smoked ≥35 cigarettes per day) compared with never smokers was 4.13 (95 percent CI: 2.49, 6.86), and the relative risk for women in the highest toenail nicotine decile compared with the lowest decile was 3.80 (95 percent CI: 2.37, 6.08). The relative risk of CHD among women reporting the highest category of smoking in this nested case-control design was similar to the risk from the whole Nurses' Health Study cohort (30), with a relative risk for CHD among women who smoked 25 or more cigarettes per day in 1980 of 4.66 (95 percent CI: 3.96, 5.47) compared with never smokers. The results from using this baseline exposure to tobacco in 1980 and updated reported smoking history in the Nurses' Health Study up to 1994 were not different (30).

Some of the observed risk using toenail nicotine levels can be explained by the reported number of cigarettes smoked (the strongest predictor of toenail nicotine levels (26)) when included in the same model, but there was still a modest, significant independent association between toenail nicotine levels and risk of CHD. This could be explained by the fact that the objective nicotine biomarker is providing unique additional CHD risk regarding exposure that is not captured by self-reported exposure to tobacco smoke. This additional risk could also be due to the measurement error associated with using subjective reporting of tobacco use and exposure to passive smoking.

In our analyses, self-reported smoking status was a slightly stronger predictor of CHD risk than toenail nicotine level and remained a strong predictor even after adjustment for toenail nicotine levels. The independent association with reported smoking status may be due to the fact that nicotine does not represent all constituents of cigarette smoke that increase the risk of CHD, even though it is correlated with them. Moreover, there may be differences in absorption and transport of nicotine that differ between nails and the vascular sites of action.

The use of biomarkers such as toenail nicotine levels thus offers a complementary exposure method to reported history of exposure, and including both measures will offer better assessment and understanding of tobacco-related health risks.

We are not aware of other studies that used biomarkers for total tobacco smoke exposure in relation to risk of CHD. Wincup et al. (31) recently used cotinine in serum for measurement of tobacco exposure in relation to risk of CHD among British men after 20 years. They found a relative risk of 1.66 (95 percent CI: 1.04, 2.68) among their highest group of exposure (light active smokers) compared with the lowest group of exposure. This was comparable to our findings (figure 1). Their population had a higher overall smoking prevalence (54 percent) and a high incidence of CHD (519 cases of 2,105 men) among nonsmokers. Those British men were exposed to high levels of secondhand smoke at baseline, which declined over time. They demonstrated a decline in relative risk to 1.04 (95 percent CI: 0.62, 1.76) after 20 years of follow-up. In the United States, major changes in laws prohibiting indoor smoking have taken place since 1982, especially in hospitals where nurses were usually exposed. Therefore, nurses who were exposed to secondhand smoke in 1982 were likely to be nonexposed in the following years of follow-up, and this can lead to attenuation of the true association.

The toenails have an advantage over other existing biomarkers of smoking, because they have the longest half-life and window of exposure. The levels represent nicotine taken up from blood by nails during growth. The slow growth rates of toenails overcome the day-to-day variability of exposure and provide a more stable estimate of average exposure, which is most relevant for illnesses related to tobacco smoke, such as CHD. The ease and low cost of collecting and storing toenail samples also make them attractive for epidemiologic studies. As with any biomarker to be used in an epidemiologic study, the cost involved in analyzing toenail nicotine levels has to be taken into consideration.

We relied on self-reports and did not have objective measures of hypertension or hypercholesterolemia. However, we have previously shown that the self-reports were highly correlated with actual measurements (32). A limitation of our study is that we did not have repeated measures of toenail nicotine levels. With the declining exposure of nonsmokers to secondhand smoke and the decline in active smoking nationwide, the measured exposure in 1982 might have misclassified exposure in later years, which likely would lead to an underestimation of the true risk between toenail nicotine levels and CHD. Because toenail nicotine levels incorporate secondhand smoke (an exposure that greatly declined in the last two decades), the attenuation from toenail nicotine levels may have been larger than from reported active smoking, which is likely to be accurately reported by nurses and less likely to change with time. This may explain the higher risk of CHD with reported active smoking.

In conclusion, our results demonstrate an increased risk of CHD with increasing toenail nicotine levels, which persisted independent of the number of reported cigarettes smoked. Similarly, self-reported smoking remained predictive of CHD after adjustment for toenail nicotine level. The use of toenail nicotine is a novel way to objectively measure exposure to tobacco smoke, and it has advantages over existing biomarkers and could become a useful test to identify high-risk individuals in the future, especially in circumstances when smoking history is not available or is subject to bias. This may improve the assessment of exposure and therefore our understanding of tobacco-related illnesses.


   ACKNOWLEDGMENTS
 
This study was funded by grant 12548 from the Flight Attendants Medical Research Foundation.

The authors would like to acknowledge Greame Mahoney for carrying out the laboratory analyses.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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