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We conducted a meta-analysis to summarize the available evidence from cohort studies on the association between excess body weight and incidence of leukemia. Studies were identified by searching the MEDLINE and EMBASE databases (1966–July 2007) and by examining the references of retrieved articles. A random-effects model was used to combine the results from individual studies. We identified 9 cohort studies with data on body mass index (BMI) or obesity in relation to incidence of leukemia. Compared with nonoverweight individuals (BMI < 25 kg/m2), the summary relative risks (RRs) of leukemia were 1.14 [95% confidence interval (CI), 1.03–1.25] for overweight individuals (BMI 25–30 kg/m2) and 1.39 (95% CI, 1.25–1.54) for obese (BMI ≥ 30 kg/m2) individuals. On a continuous scale, a 5 kg/m2 increase in BMI was associated with a 13% increased risk of leukemia (RR, 1.13; 95% CI, 1.07–1.19). In a meta-analysis of 4 studies reporting results on subtypes of leukemia, the summary RRs associated with obesity were 1.25 (95% CI, 1.11–1.41) for chronic lymphocytic leukemia, 1.65 (95% CI, 1.16–2.35) for acute lymphocytic leukemia, 1.52 (95% CI, 1.19–1.95) for acute myeloid leukemia and 1.26 (95% CI, 1.09–1.46) for chronic myeloid leukemia. This meta-analysis indicates that excess body weight is associated with an increased risk of developing leukemia. © 2007 Wiley-Liss, Inc.
Excess body weight has been associated with increased risk of a wide range of malignancies, including cancer of the endometrium, breast (in postmenopausal women), colon, kidney, esophagus, pancreas, liver and gallbladder.1–4 Emerging epidemiologic evidence also suggests that excess body weight may be a risk factor for hematologic cancers, including non-Hodgkin's lymphoma,5 multiple myeloma6 and possibly leukemia. The aim of this study was to summarize the available evidence from cohort studies on the relations of overweight and obesity, as measured by body mass index (BMI), with the incidence of leukemia.
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The 9 cohort studies12–20 that were included in the meta-analysis were published between 1994 and 2007 (Table I). Five were conducted in Europe, 2 in the United States, 1 in Australia and 1 in Korea. Weight and height were directly measured in 5 studies13, 17–20 and self-reported in 1 study15; 3 studies were based on a discharge diagnosis of obesity.12, 14, 16
Table I. Characteristics of Cohort Studies Included in the Meta-Analysis of BMI and Leukemia Incidence
|Study||Country||Study participants||Cases||ICD codes for leukemia||BMI (kg/m2) categories||Adjustments|
|BMI reference||BMI overweight||BMI obesity|
|Møller et al., 199412||Denmark||43,965 men and women||51||Not specified||Nonobese||–||Obese1||Age|
|Tulinius et al., 199713||Iceland||11,366 men||33||ICD-7 code 204||–2||–2||–2||Age|
|Wolk et al., 200114||Sweden||28,129 men and women||39||ICD-7 code 204||Nonobese||–||Obese1||Age, calendar year|
|Ross et al., 200415||United States||37,627 women||194||Not specified||18.5–24.9||25.0–29.9||≥30.0||Age, physical activity|
|Samanic et al., 200416||United States||4,500,700 male veterans||9790||ICD-8/9 codes 204–208||Nonobese||–||Obese1||Age, calendar year|
|MacInnis et al., 200517||Australia||40,909 men and women||106||ICD-10 morphology codes 9821, 9823, 9861, 9863, 9866–9868, 9874, 9891, 9895, 9945||<25.0||25.0–29.9||≥30.0||Age, country of birth, education|
|Oh et al., 200518||Korea||781,283 men||200||Not specified||18.5–22.9||25.0–29.93||≥30.0||Age, area of residence, family history of cancer, smoking, exercise, alcohol|
|Engeland et al., 200719||Norway||1,999,978 men and women||6564||Not specified||18.5–24.9||25.0–29.9||≥30.04||Age, birth cohort|
|Fernberg et al., 200720||Sweden||336,381 men||372||Not specified||18.6–24.9||25.0–29.9||≥30.0||Age, snuff use, smoking|
Relative risk estimates of leukemia for overweight and obese individuals compared with those of normal weight for individual studies and all studies combined are shown in Figure 1. Compared with normal weight, the summary RRs of leukemia were 1.14 (95% CI, 1.03–1.25) for overweight and 1.39 (95% CI, 1.25–1.54) for obesity. There was evidence of heterogeneity among study-specific results for obesity but not overweight (Fig. 1). The positive relation between obesity and risk of leukemia remained after excluding the 3 cohort studies based on a discharge diagnosis of obesity12, 14, 16 (RR, 1.23; 95% CI, 1.12–1.34). Obesity was associated with a statistically significant increased risk of leukemia both among men (RR 1.46; 95% CI, 1.36–1.56; n = 6 studies) and women (RR 1.19; 95% CI, 1.09–1.31; n = 4 studies). There was no indication of publication bias (Egger's test: p = 0.61 for overweight; p = 0.47 for obesity). On a continuous scale, a 5 kg/m2 increment in BMI was associated with a statistically significant 13% increased risk of leukemia (RR, 1.13; 95% CI, 1.07–1.19; n = 6 studies), with no heterogeneity among studies (p = 0.35).
Meta-analysis of 4 studies that provided results by leukemia subtypes15, 16, 19, 20 found that obesity was associated with a statistically significant increased risk of all subtypes, including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia and chronic myeloid leukemia (Fig. 2). There was significant heterogeneity only among study-specific results for acute myeloid leukemia (Fig. 2).
Figure 2. Association of obesity with incidence of leukemia subtypes. Tests for heterogeneity: chronic lymphocytic leukemia, p = 0.21, I2 = 31.2%; acute lymphocytic leukemia, p = 0.37, I2 = 6.8%; acute myeloid leukemia, p < 0.001, I2 = 79.3%; chronic myeloid leukemia, p = 0.51, I2 = 0%.
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- Material and methods
This meta-analysis of cohort studies provides evidence that excess body weight may be a risk factor for leukemia. Summary results indicate that overweight and obese individuals have a 14 and 39%, respectively, greater risk of leukemia compared to nonoverweight individuals. Obesity was directly associated with the risk of leukemia in both men and women and with all subtypes of leukemia.
The major strength of this meta-analysis is the inclusion of prospective cohort studies, which eliminated the possibility that the observed association between excess body weight and risk of leukemia was due to recall and selection biases. This meta-analysis also has some potential limitations. First, the possibility that the results were affected by confounding from other risk factors cannot be ruled out. Only 2 studies adjusted for smoking.18, 20 However, any confounding from smoking would probably tend to attenuate the positive association between body weight and risk of leukemia, and the increase in risk observed in this meta-analysis may have been a conservative estimate. Another limitation is that only 4 studies reported results by subtypes of leukemia, leading to relatively low statistical power in analysis relating obesity to leukemia subtypes. Finally, in a meta-analysis of published studies, publication bias could be a problem because small studies with null results tend not to be published. Although we found no evidence of such bias, the test for publication bias has limited power when the number of studies is small. The presence of possible publication bias could have led to an overestimation of the true relationship between excess body weight and risk of leukemia.
Obesity has also been associated with an increased risk of mortality from leukemia. In a large prospective cohort study of more than 900,000 US adults,9 men with a BMI of 35 kg/m2 or more had a statistically significant 70% higher risk of death from leukemia; no association was observed among women. Results from another cohort study of 35,420 US adults showed a positive dose-response relationship between BMI and mortality from leukemia in both men and women.11
The biologic mechanism underlying the observed relations of overweight and obesity with increased risk of leukemia is unclear. A metabolic consequence of obesity is insulin resistance followed by an increased pancreatic insulin secretion.26 Insulin may promote tumorigenesis directly through insulin receptors in (pre)neoplastic target cells, or indirectly by increasing bioavailable insulin-like growth factor-I (IGF-I) levels.26 Almost all normal and neoplastic hematopoietic cells express the IGF receptors.27 IGF-I is involved in hematopoeisis and is mitogenic for cell lines of myeloid and lymphoid leukemias.27 The increased risk of leukemia in obese individuals may also be due to impaired immune function and chronic inflammation associated with obesity.28
In summary, findings from this meta-analysis of prospective studies provide evidence that excess body weight may increase the risk of developing leukemia. Whether the relation varies by leukemia subtypes warrants further investigation.