In this large European cohort study, general and abdominal adiposity were independently related to the risk of death. The associations of BMI with the risk of death were J-shaped, with higher risks of death observed in the lower and upper BMI categories than in the middle categories. In contrast, once general adiposity was adjusted for, abdominal fat distribution was positively associated with the risk of death. These associations tended to be stronger among participants with a lower BMI than among those with a higher BMI. Thus, measurement of both general and abdominal adiposity provides a better assessment of the risk of death, particularly among people with a lower BMI.

The most appropriate adiposity markers for assessing the risk of disease and death are debated.4,32 Waist circumference and BMI are highly correlated and when considered individually reflect the extent of both abdominal and general obesity. However, the large sample in our study enabled us to estimate with sufficient precision the effect of abdominal adiposity on the risk of death independently of general obesity. The waist-to-hip ratio is less strongly related to BMI than is waist circumference and is therefore a more specific surrogate for fat distribution. Although the waist-to-hip ratio may therefore be preferred as a predictor of the risk of death, in addition to BMI, because it has less potential for collinearity, the use of waist circumference has been predominantly proposed in the past decade, largely because waist circumference is easier to measure and to interpret than the waist-to-hip ratio.2,33

The current results underscore the importance of assessing the distribution of body fat even among persons of normal weight and challenge the use of cutoff points to define abdominal obesity, at least when they are used to predict the risk of death.2,34 Our finding of a positive association between waist circumference and the risk of death among participants of normal weight may also explain why studies have been unable to show a linear relationship between BMI and the risk of death across the entire range of BMI values.

Like previous studies, our study showed that general obesity was more strongly related to the risk of death among participants who had never smoked, whereas underweight was more strongly related to the risk of death among current smokers; these results may reflect the finding that smokers have a lower body weight but a higher risk of death than nonsmokers.15,17,35 In contrast, after adjustment for BMI, the association of waist circumference with the risk of death was stronger among smokers. Smokers tend to have a metabolically more adverse fat-distribution profile, with higher central adiposity, than nonsmokers.36 Older persons may be more likely than younger persons to have underlying but undiagnosed chronic diseases that are related to a lower BMI and an increased risk of death. Obesity appeared to be more strongly related to the risk of death among younger men than among older men, whereas no such difference was observed among women. The reasons for these sex differences are unclear and may reflect biologic factors or the play of chance. It is also important to note that the absolute risk of death in the reference category varied across subgroups. For example, although general adiposity was more strongly related to the risk of death among people who had never smoked than among current smokers, the absolute risk of death was higher among current smokers (data not shown).

Adipose tissue, particularly tissue from visceral-fat deposits, secretes potential mediators in the development of chronic diseases1; this process may explain why abdominal fat distribution was related to the risk of death independently of BMI. Body mass is more closely related to the amount of visceral fat in men than in women,37 which may be among the reasons that the relative risk of death among participants with a high BMI was higher for men than for women. The increased risk of death among participants with a low BMI could be the result of low muscle mass, since even at a low BMI, waist circumference was positively related to the risk of death. As in the present study, a recent report suggested that the increase in the risk of death associated with a low BMI is driven primarily by respiratory and other causes, whereas the increased risk associated with a high BMI is driven by cardiovascular causes and cancer.18 Although abdominal adiposity is related to chronic inflammation, which may lead to the development of chronic bronchitis and other diseases, the mechanisms for the strong positive associations with deaths from respiratory and other causes are unclear.38

Our study has certain limitations. Although people who had a history of cancer, heart disease, or stroke were excluded, our analysis may have included a number of participants who had other serious diseases that could potentially confound the observed associations. Nevertheless, we believe that the number of participants with other serious diseases at baseline was small because it is unlikely that such persons would decide to participate in a long-term cohort study. This assumption is indirectly supported by the low prevalence of cancer, heart disease, and stroke in the original EPIC study population. The association of adiposity with the risk of death may vary with a longer follow-up period; however, it would probably become stronger, as suggested by our sensitivity analysis.

The improvement in the prediction of risk by the addition of waist circumference or waist-to-hip ratio to BMI was small with respect to the C statistic, as would be expected, since the C statistic is very insensitive to the detection of true predictors.30,39 In contrast, and clinically more important,30 the addition of waist circumference or waist-to-hip ratio to BMI more accurately stratified participants into higher-risk and lower-risk categories.

The causes of heterogeneity across centers, driven by the Greek cohort, are unclear and may reflect differences in the way in which anthropometric measurements were performed, biologic diversity among different populations, or the play of chance. Nevertheless, the relative-risk estimates for the overall cohort did not change substantially when the participants from Greece were excluded from the analysis.

The use of overall mortality and broad categories of cause-specific mortality in our analysis of risk may limit interpretations of the causes of the associations. Nevertheless, such research is crucial for estimating whether reductions in the prevalence of adiposity would affect a population's mortality. Although the level of accuracy for the coding of deaths from cancer and circulatory causes on the basis of information from death certificates is high, it may be lower for the coding of deaths from respiratory causes.40 Therefore, the analyses according to the cause of death have to be interpreted cautiously. In addition, imperfect follow-up procedures may have resulted in the erroneous classification of some deceased participants as alive. However, we believe that this number was negligibly small, and, given the large sample, the reduction in sensitivity would have no substantial effect on the estimates of relative risk. Finally, although we adjusted our analyses for several variables, because of the observational nature of the study, we cannot exclude the possibility of residual confounding.

In conclusion, the findings of our study suggest that general and abdominal adiposity are both associated with the risk of death. The results support the use of waist circumference or waist-to-hip ratio in addition to BMI in the assessment of the risk of death, particularly among persons with a low BMI.