Published online before print March 24, 2008, doi: 10.1161/CIRCULATIONAHA.107.739714
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(Circulation. 2008;117:1658-1667.)
© 2008 American Heart Association, Inc.
Epidemiology |
Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality
Sixteen Years of Follow-Up in US Women
From the Epidemiology Branch, Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Bethesda, Md (C.Z.); Division of Preventive Medicine (K.M.R.) and Channing Laboratory (R.M.v.D., F.B.H.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and Departments of Nutrition (R.M.v.D., T.Y.L., F.B.H.) and Epidemiology (F.B.H.), Harvard School of Public Health, Boston, Mass.
Reprint requests to Cuilin Zhang, MD, PhD, Epidemiology Branch, Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, 6100 Executive Blvd, Room 7B03, MSC 7510, 9000 Rockville Pike, Bethesda, MD 20892–7510. E-mail zhangcu{at}mail.nih.gov or nhbfh@channing.harvard.edu
Received September 11, 2007; accepted January 4, 2008.
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Abstract |
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Background— Accumulating evidence indicates that abdominal adiposity is positively related to cardiovascular disease (CVD) risk and some other diseases independently of overall adiposity. However, the association of premature death resulting from these diseases with abdominal adiposity has not been widely studied, and findings are inconsistent.
Methods and Results— In a prospective cohort study of 44 636 women in the Nurses’ Health Study, associations of abdominal adiposity with all-cause and cause-specific mortality were examined. During 16 years of follow-up, 3507 deaths were identified, including 751 cardiovascular deaths and 1748 cancer deaths. After adjustment for body mass index and potential confounders, the relative risks across the lowest to the highest waist circumference quintiles were 1.00, 1.11, 1.17, 1.31, and 1.79 (95% confidence interval [CI], 1.47 to 1.98) for all-cause mortality; 1.00, 1.04, 1.04, 1.28, and 1.99 (95% CI, 1.44 to 2.73) for CVD mortality; and 1.00, 1.18, 1.20, 1.34, and 1.63 (95% CI, 1.32 to 2.01) for cancer mortality (all P<0.001 for trend). Among normal-weight women (body mass index, 18.5 to <25 kg/m2), abdominal obesity was significantly associated with elevated CVD mortality: Relative risk associated with waist circumference 
88 cm was 3.02 (95% CI, 1.31 to 6.99) and for waist-to-hip ratio >0.88 was 3.45 (95% CI, 2.02 to 6.92). After adjustment for waist circumference, hip circumference was significantly and inversely associated with CVD mortality.
Conclusions— Anthropometric measures of abdominal adiposity were strongly and positively associated with all-cause, CVD, and cancer mortality independently of body mass index. Elevated waist circumference was associated with significantly increased CVD mortality even among normal-weight women.
Key Words: adiposity • cancer cardiovascular diseases • mortality • obesity • waist-hip ratio
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Introduction |
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In parallel with the increase in overall body adiposity in the US population, the prevalence of abdominal obesity increased substantially during the past 15 years.1 More than half of US adults had abdominal obesity in the period of 2003 to 2004.1 Growing evidence suggests that abdominal obesity is particularly detrimental.2 Greater abdominal adiposity is strongly associated with insulin resistance, dyslipidemia, and systematic inflammation, which play essential roles in the pathogenesis of cardiovascular disease (CVD), metabolic syndrome, and certain cancers.2,3
Editorial p 1624
Clinical Perspective p 1667
Waist circumference (WC) and waist-to-hip ratio (WHR) are widely used as indirect measures of abdominal or central adiposity in epidemiological studies. Although the definition of abdominal obesity remains in dispute, the cutoffs for WC (102 cm for men, 88 cm for women) and WHR (0.95 for men, 0.88 for women) were recommended by the American Heart Association and the US Department of Agriculture. Recently, waist-to-height ratio was suggested as an alternative to WHR because it provides a correction for body frame size using height, which is more conveniently measured than hip circumference.4–6 Accumulating evidence indicated that the above measures of abdominal adiposity were significantly and positively associated with risks for chronic diseases such as CVD, diabetes mellitus, and some cancers independently of overall adiposity.7 The association of these measures with mortality, however, has not been widely studied, and findings have been controversial.8–12 The inconsistencies of findings can be due to differences in study populations and sampling (eg, age, gender, distribution of lifestyle factors related to adiposity such as smoking status, inclusion of individuals with chronic diseases related to adiposity, and duration of follow-up), measures of abdominal adiposity, and analytic approaches. Furthermore, few studies have investigated the joint and independent effects of abdominal and overall adiposity. With the consideration of major factors contributing to the heterogeneity of previous findings, we investigated several measures of abdominal adiposity—WC, WHR, and waist-to-height ratio—in relation to all-cause, CVD, and cancer mortality during the 16 years of follow-up of the Nurses’ Health Study.
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Methods |
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Population
The Nurses’ Health Study cohort was established in 1976 when 121 700 female registered nurses 30 to 55 years of age who resided in 11 large US states completed a mailed questionnaire on their medical history and lifestyle. The cohort continues to be followed up every 2 years by questionnaire to update information on potential risk factors and to identify cases of newly diagnosed diseases (ie, CVD, diabetes mellitus, and cancers). We restricted our analysis to those 44 636 women who reported WC in the 1986 questionnaire who also were free of a prior history of CVD and cancer. Age, body weight, and major social demographic and clinical characteristics of those who reported WC were not appreciably different from those who did not report it.
Assessment of Overall and Abdominal Adiposity
As a measure of overall adiposity, we calculated body mass index (BMI) as weight in kilograms divided by the square of height in meters (kg/m2). Self-reported weights were validated in a subsample of 184 Nurses’ Health Study participants living in the Boston, Mass, area and were highly correlated with actual measured weights (r=0.96; [mean difference: self-reported weight–measured weight]=–1.5 kg [SD, 2.98 kg]).13 In 1986, Nurses’ Health Study participants measured and reported measurements of their waist (at the umbilicus) and hip circumference (the largest circumference) to the nearest quarter-inch. To validate these measurements, self-reported measures in a sample of 140 nurses were compared with 2 standardized measurements taken 
6 months apart by technicians who visited participants in their homes. The distributions for age, BMI, and other sociodemographic characteristics of women in this sample are similar to those in the parent cohort. The correlations between self-reported and technician-measured circumferences were 0.89 for the waist (mean difference: [self-reported–measured]=–0.05 in [SD, 1.99 in]), 0.84 for the hip (mean difference: [self-reported–measured]=–0.54 in [SD, 2.01 in]), and 0.70 for the WHR (mean difference: [self-reported–measured]=–0.011 [SD, 0.049]).14 In addition, no significant linear trends in correlations were present for WC across quartiles of BMI, and no effect modification was noted by age or BMI on the validity of self-reported circumference measures.
Ascertainment of Covariates
Every 2 years, we update participants’ smoking status, menopausal status, and postmenopausal hormone use status. We also inquire about physician-diagnosed hypertension and high cholesterol. In a subsample, self-reports were compared with medical records and found to be highly accurate.15 Alcohol consumption was assessed by a validated food frequency questionnaire that included questions about average daily consumption of beer, wine, and spirits during the previous year.16 We asked women about the average time spent per week on the following physical activities: walking, jogging, running, bicycling, lap swimming, playing tennis or squash, and calisthenics.17 In a validation study, the correlation between physical activity reported on the 1-week recalls and that reported on the questionnaire was 0.79.18 The correlation between moderate to vigorous activity reported in diaries and that reported on questionnaire was 0.62.
End Points
Deaths were reported by next of kin and the postal system or ascertained through the National Death Index. Follow-up for deaths was >98% complete.19 For all deaths, we sought death certificates and, when appropriate, requested permission from the next of kin to review medical records (subject to state regulations). Underlying cause of death was assigned according to the International Classification of Diseases, eighth revision (ICD-8). Deaths were divided into those resulting from CVD (ICD-8 codes 390.0 to 458.9 and 795.0 to 795.9), cancer (ICD-8 codes 140.0 to 207.9), and other causes.
Statistical Analysis
We grouped women into quintile categories of WC, WHR, waist-to-height ratio, or hip circumference at baseline (1986). Participants contributed person-time from the date of return of the 1986 questionnaires until the date of death or June 1, 2002, whichever came first. The relative risk (RR) was calculated as the rate for a given category of the above measurements compared with the lowest category. Age-adjusted analyses were conducted with 5-year age categories using the Mantel-Haenszel method.20 Cox proportional-hazards regression21 was used to adjust for age and other potential confounders at baseline, including smoking, alcohol use, menopausal status/postmenopausal hormone use, physical activity, and parental history of myocardial infarction (MI) <60 years of age. To examine whether the relationship between abdominal obesity and mortality was affected by overall adiposity, we further adjusted for BMI (<18.5, 18.5 to 24.9, 25 to 29.9, 30 to 34.9, 35 kg/m2). In sensitivity analysis, we also fitted BMI as a continuous variable and included a nonlinear term of age (age2) in Cox regression models. In addition, we used restricted cubic spline transformations with 4 knots to flexibly model the relation between measurements of abdominal adiposity (as continuous variables) and mortality, avoiding the need for prior specification of the risk function or the location of a threshold exposure value.22
We evaluated whether the association between abdominal adiposity and mortality was modified by major baseline characteristics such as age (
55 years versus >55 years), smoking status (never versus ever), menopause status (premenopausal versus postmenopausal), and overall adiposity (BMI <25 versus 25 kg/m2) in stratified analyses. Tests of trend were conducted using the median value for each category of measurements of abdominal adiposity as a continuous variable in multivariate models. Tests for interaction were performed with likelihood ratio tests by comparing 2 nested multivariate models with and without the interaction term. All statistical analyses were conducted with SAS version 8.2 (SAS Institute Inc, Cary, NC). All probability values were 2 sided.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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During 16 years of follow-up (687 519 person-years), we identified 3507 deaths, including 751 CVD deaths and 1748 cancer deaths. At baseline (1986), higher levels of WC, WHR, and waist-to-height ratio were associated with lower levels of physical activity and a lower likelihood of postmenopausal hormone use but with a greater likelihood of clinical hypertension and hypercholesterolemia (Table 1). The different anthropometric measures of abdominal obesity were highly correlated (Table 2). In addition, these measures were all significantly correlated with BMI, although the correlation for WHR (r=0.33) was not as strong as those with WC (r=0.81) and waist-to-height ratio (r=0.83).
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After adjustment for age, smoking, and other covariates, both increasing WC and WHR were strongly associated with a graded increase in all-cause mortality (Tables 3 and 4
). In general, the association for WC became stronger after adjustment for BMI. Similar results were observed in sensitivity analysis when BMI was fitted as continuous variable or when a nonlinear term of age (age2) was added to regression models. Spline regression showed linear association of both WC and WHR with all-cause, CVD, and cancer mortality (Figure 1), and probability values for test for departure from linearity were not significant (P>0.05). In stratified analyses, the associations of WC and WHR with mortality were not appreciably different between never and ever smokers, between younger (55 years of age) and older (>55 years of age) women, and between premenopausal and postmenopausal women. Even among women who were neither overweight nor obese, both WC and WHR were strongly associated with mortality. Similar associations were observed between waist-to-height ratio and mortality. After adjustment for BMI and other covariates, RR and 95% confidence interval (CI) across the lowest to the highest quintile of waist-to-height ratio were 1.00, 1.09, 1.09, 1.22, and 1.54 (95% CI, 1.32 to 1.78) for all-cause mortality; 1.00, 0.81, 0.78, 1.20, and 1.52 (95% CI, 1.11 to 2.09) for CVD mortality; and 1.00, 1.33, 1.21, 1.28, and 1.56 (95% CI, 1.26 to 1.93) for cancer mortality (all P<0.001 for trend).
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The association of hip circumference with CVD and cancer mortality was J shaped after adjustment for age, smoking status, physical activity, and other lifestyle and medical covariates so that the lowest mortality was observed among those in the third quintile (Table 5). After adjustment for WC, greater hip circumference was associated with lower all-cause and CVD mortality but not cancer mortality.
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We next examined the joint effects of abdominal (WC and WHR) and overall (BMI) adiposity using the currently recommended cutoffs for BMI (25 or 30 kg/m2), WC (35 in [88 cm]), and WHR (0.88) (Figure 2). Because smokers tend to weigh less but have much higher mortality rates than nonsmokers, which can lead to the artifact of an apparent elevation in risk of mortality among leaner individuals, we restricted the analyses to never smokers. In addition, because a very low BMI in some older adults may reflect ill health that we could not completely control for even after excluding prevalent cancer and heart disease, we excluded underweight women (BMI <18.5 kg/m2). The highest mortality risk was observed among those who had both abdominal and overall obesity. However, even among normal-weight women, abdominal obesity was associated with significantly higher risk for CVD mortality: RR associated with larger WC 88 cm [35 in] was 3.02 (95% CI, 1.31 to 6.99) and for WHR >0.88 was 3.45 (95% CI, 2.02 to 6.92). In addition, within each category of WC or WHR, higher BMI was associated with increased total, CVD, and cancer mortality.
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Discussion |
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In the present study of a large prospective cohort of US women, we observed a monotonic dose–response relationship between abdominal adiposity, as measured by WC, WHR, or waist-to-height ratio, and the risk of death among both younger (<55 years of age) and older (
55 years of age) women and among both never and ever smokers. This positive association persisted in normal-weight women. The prospective design and high rate of follow-up in this study minimized the possibility of recall bias or bias resulting from loss of follow-up. Furthermore, the large size of the study increased the precision of the RR estimates, and the extensive information on potential confounders allowed us to control for confounding in detail. One potential limitation is that the anthropometric measures of adiposity in the present study were by self-report. However, the validity of self-reported weight and waist and hip circumferences compared with technician measurements was high in this population of health professionals.15,23 Because of the prospective design of this study, misclassification would be nondifferential and expected to bias the risk estimate toward the null. A major concern in analyzing the relationship between obesity and subsequent mortality is the problem of reverse causation (ie, weight loss can be the result, rather than the cause, of underlying illness).24 To address this concern, we excluded participants with existing CVD and cancer at baseline.
Although a number of epidemiological studies have demonstrated that measures of abdominal adiposity significantly predict chronic diseases such as CVD and diabetes mellitus independently of overall body adiposity,7 the associations of these measures with premature death have not been widely studied, and previous findings8–12 have been inconsistent. The inconsistencies of findings may be related to differences in study populations and sampling, measures of abdominal adiposity, and analytic approaches. Our findings are in general consistent with those supporting an independent contribution of body fat distribution to mortality and the importance of abdominal adiposity in predicting mortality in women. In the Iowa Women’s Health Study,9 both WC and WHR were significantly associated with mortality, particularly coronary heart disease mortality. Likewise, in both a Danish cohort10 and a Swedish cohort12 of middle-aged and older women, abdominal adiposity was strongly and positively associated with all-cause mortality after adjustment for BMI. The follow-up time was short, and only findings related to WC were reported in the Danish cohort, whereas only findings for WHR were reported in the Swedish cohort. In a recent study of elderly women (75 years of age) in the United Kingdom,8 WHR but not WC was positively related to mortality in nonsmoking women only, mainly because of cardiovascular mortality. By contrast, in a relatively small Dutch cohort of elderly women,11 neither WHR nor WC was significantly associated with all-cause mortality. Data on the association of abdominal adiposity and fat distribution with overall cancer mortality are sparse. In the Iowa study,9 neither WC nor WHR was significantly associated with cancer mortality after adjustment for multiple risk factors. Association of measures of abdominal adiposity with cancer mortality was not reported in most studies of abdominal adiposity and mortality.8,10–12 With >600 000 person-years of follow-up and 3507 deaths, ours is one of the largest studies with the longest follow-up duration on abdominal adiposity and all-cause and cause-specific mortality.
The metabolic effects of abdominal adiposity are well established. Greater abdominal adiposity is closely associated with adverse metabolic profiles such as insulin resistance, dyslipidemia, and systematic inflammation, which play essential roles in the pathogenesis of CVD, diabetes mellitus, and certain cancers.2,3 Of note, the association of abdominal obesity with these adverse metabolic profiles persisted among normal-weight women.25 For instance, higher WC was significantly related to higher total cholesterol, low-density lipoprotein cholesterol and triglyceride levels, higher systolic and diastolic blood pressures, and higher fasting glucose levels among normal-weight women.
There have been continuous debates on whether WC or WHR is a better measure of abdominal adiposity in predicting health risks in epidemiological studies. WC as a measure of both subcutaneous and visceral fat can be measured easily. However, WC also is correlated with body frame size; thus, WHR often is used instead.26 In the present study, both measures were significantly associated with all-cause, CVD, and cancer mortality. WHR did not seem to provide substantially better prediction than WC. Because WHR requires measures of both waist and hip circumference and is more difficult to interpret, WC is more applicable in clinical practice.
The inverse association of hip circumference with mortality (mainly CVD mortality) after adjustment for WC is of interest. It suggests that given a certain level of WC, a greater hip circumference, may be associated with lower CVD mortality. Such an association may be explained by larger peripheral fat mass associated with greater hip circumference.7 Recent studies suggested that the femoral-gluteal fat depot, for a given amount of abdominal fat, plays a protective role by acting as a "sink" for circulating free fatty acids27; the femoral-gluteal region is more likely to effectively take up free fatty acids from the circulation and is less likely to release them readily.7 Because of the increased free fatty acid uptake in the femoral-gluteal region resulting from a larger hip circumference, detrimental ectopic fat storage in tissues or organs (ie, the liver, skeletal muscle, and pancreas) and subsequent adverse metabolic effects may be prevented.28 Indeed, studies using dual-energy x-ray absorptiometry or computed tomography to estimate fat and muscle content at the legs found that subcutaneous fat at the legs was associated with a more favorable cardiovascular risk profile (for a given amount of abdominal fat).29–32
Our study population consisted of registered nurses. The relative homogeneity in occupation and education can reduce confounding by socioeconomic factors. Because the study population was predominantly white, our findings require confirmation in other ethnic groups. In a recent study among Chinese women,33 a significant positive association between WHR and mortality also was observed.
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Conclusions |
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Our data indicate that abdominal adiposity is significantly and positively associated with all-cause and cause-specific mortality. Greater WC or WHR is associated with increased CVD mortality even in normal-weight women. Although maintaining a healthy weight should continue to be a cornerstone in the prevention of chronic diseases and premature death,34 it is equally importanty to maintain a healthy waist size and prevent abdominal obesity.
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Acknowledgments |
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We thank the participants of the Nurses’ Health Study for their continued participation and Drs Walter C. Willett and JoAnn E. Manson for their valuable comments on the manuscript.
Sources of Funding
This study is supported by National Institutes of Health grants DK58845, CA87969, and HL34594. Dr Zhang was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Disclosures
None.
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References |
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Footnotes |
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Guest Editor for this article was Robert Eckel, MD.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
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Circulation 2008 117: 1621.
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S. E. Litwin Which Measures of Obesity Best Predict Cardiovascular Risk? J. Am. Coll. Cardiol., August 19, 2008; 52(8): 616 - 619. [Full Text] [PDF]
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G. K. Andrikopoulos and S. Tzeis Modification of Cardiometabolic Risk Through Cannabinoid Type-1 Receptor Antagonism Angiology, August 1, 2008; 59(2_suppl): 44S - 48S. [Abstract] [PDF]
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A. J. Cameron and P. Z. Zimmet Expanding Evidence for the Multiple Dangers of Epidemic Abdominal Obesity Circulation, April 1, 2008; 117(13): 1624 - 1626. [Full Text] [PDF]
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