Non-Hodgkin lymphoma and obesity: a pooled analysis from the InterLymph Consortium

Abstract

Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL, self-reported anthropometric data on weight and height from over 10,000 cases of NHL and 16,000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m(-2) or more, was not associated with NHL overall (pooled OR = 1.00, 95% confidence interval (CI) 0.70-1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR = 1.80, 95% CI 1.24-2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25-29.9 kg m(-2)) and obese (BMI 30-39.9 kg m(-2)), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI < 18.5 kg m(-2)). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m(-2) rise in BMI above 18.5 kg m(-2). BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR = 1.19, 95% CI 1.06-1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation.

Figure 1

Box-Whisker Plot of Body Mass Index among Controls by Study. Body mass index considered to be: Underweight if <18.5 kg m⁻²; Normal weight-for-height if 18.5–24.99 kg m⁻²; Grade 1 Overweight if 25–29.99 kg m⁻²; Grade 2 Obese if 30–39.99 kg m⁻²; and Grade 3 Obese if ≥40 kg m⁻² (55).

Figure 2

Figure 2(a). Meta-analysis of the risk of NHL associated with BMI <18.5 kg m⁻² (Underweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=13.0, p=0.73; Variation in odds ratios (OR) attributable to heterogeneity: I²= 0.0%. For continents: North America: Q=1.04, p=0.90, I²=0.0%; Northern Europe: Q=7.87, p=0.25, I²=23.7%; Southern Europe: Q=1.03, p=0.80, I²=0.0%; Asia (Japan): Q=1.38, p= 0.24, I²=27.5%. Test for heterogeneity between continents: Q=1.82, p=0.61. Pooled odds ratios by study design were: Population-based studies: OR=0.91, 95% CI 0.68–1.21, Q=6.75, p=0.56, I²=0.0%; Clinic-based studies: OR=0.92, 95% CI 0.65–1.31, Q=1.47, p=0.48, I²=0.0%; Hospital-based studies: OR=0.67, 95% CI 0.39–1.17, Q=3.79, p=0.58, I²=0.0%. Test for heterogeneity between study designs: Q=1.04, p=0.59. Figure 2(b). Meta-analysis of the risk of NHL associated with BMI 25–29.99 kg m⁻² (Grade 1 overweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=60.0, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=70.0%. For continents: North America: Q=2.76, p=0.60, I²=0.0%; Northern Europe: Q=25.0, p=0.001, I²=72.1%; Southern Europe: Q=8.59, p=0.04, I²=65.1%; Asia (Japan): Q=0.02, p=0.90, I²=0.0%. Test for heterogeneity between continents: Q=23.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=0.97, 95% CI 0.82–1.14, Q=41.6, p<0.001, I²=80.8%; Clinic-based studies: OR=0.99, 95% CI 0.82–1.20, Q=0.44, p=0.80, I²=0.0%; Hospital-based studies: OR=0.91, 95% CI 0.72–1.16, Q=14.0, p=0.03, I²=57.1%. Test for heterogeneity between study designs: Q=3.93, p=0.14. Figure 2(c). Meta-analysis of the risk of NHL associated with BMI 30–39.99 kg m⁻² (Grade 2 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=59.7, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=69.8%. For continents: North America: Q=8.18, p=0.08, I²=51.1%; Northern Europe: Q=18.1, p=0.01, I²=61.2%; Southern Europe: Q=7.88, p=0.05, I²=62.0%; Asia (Japan): Q=0.01, p=0.93, I²=0.0%. Test for heterogeneity between continents: Q=25.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=1.06, 95% CI 0.83–1.34, Q=41.3, p<0.001, I²=80.7%; Clinic-based studies: OR=1.22, 95% CI 0.90–1.67, Q=0.03, p=0.99, I²=0.0%; Hospital-based studies: OR=0.77, 95% CI 0.60–0.98, Q=8.51, p=0.20, I²=29.5%. Test for heterogeneity between study designs: Q=9.81, p=0.007. Figure 2(d). Meta-analysis of the risk of NHL associated with BMI ≥40 kg m⁻² (Grade 3 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=21.9, p=0.15; Variation in odds ratios (OR) attributable to heterogeneity: I²=26.8%. For continents: North America: Q=2.89, p=0.58, I²=0.0%; Northern Europe: Q=15.3, p=0.03, I²=54.4%; Southern Europe: Q=0.69, p=0.88, I²=0.0%. Test for heterogeneity between continents: Q=2.91, p=0.23. Pooled odds ratios by study design were: Population-based studies: OR=1.33, 95% CI 0.88–2.00, Q=11.4, p=0.18, I²=29.7%; Clinic-based studies: OR=0.57, 95% CI 0.26–1.22, No test for heterogeneity as only 1 study; Hospital-based studies: OR=0.51, 95% CI 0.25–1.05, Q=2.07, p=0.91, I²=0.0%. Test for heterogeneity between study designs: Q=8.41, p=0.015.

Figure 2

Figure 2(a). Meta-analysis of the risk of NHL associated with BMI <18.5 kg m⁻² (Underweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=13.0, p=0.73; Variation in odds ratios (OR) attributable to heterogeneity: I²= 0.0%. For continents: North America: Q=1.04, p=0.90, I²=0.0%; Northern Europe: Q=7.87, p=0.25, I²=23.7%; Southern Europe: Q=1.03, p=0.80, I²=0.0%; Asia (Japan): Q=1.38, p= 0.24, I²=27.5%. Test for heterogeneity between continents: Q=1.82, p=0.61. Pooled odds ratios by study design were: Population-based studies: OR=0.91, 95% CI 0.68–1.21, Q=6.75, p=0.56, I²=0.0%; Clinic-based studies: OR=0.92, 95% CI 0.65–1.31, Q=1.47, p=0.48, I²=0.0%; Hospital-based studies: OR=0.67, 95% CI 0.39–1.17, Q=3.79, p=0.58, I²=0.0%. Test for heterogeneity between study designs: Q=1.04, p=0.59. Figure 2(b). Meta-analysis of the risk of NHL associated with BMI 25–29.99 kg m⁻² (Grade 1 overweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=60.0, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=70.0%. For continents: North America: Q=2.76, p=0.60, I²=0.0%; Northern Europe: Q=25.0, p=0.001, I²=72.1%; Southern Europe: Q=8.59, p=0.04, I²=65.1%; Asia (Japan): Q=0.02, p=0.90, I²=0.0%. Test for heterogeneity between continents: Q=23.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=0.97, 95% CI 0.82–1.14, Q=41.6, p<0.001, I²=80.8%; Clinic-based studies: OR=0.99, 95% CI 0.82–1.20, Q=0.44, p=0.80, I²=0.0%; Hospital-based studies: OR=0.91, 95% CI 0.72–1.16, Q=14.0, p=0.03, I²=57.1%. Test for heterogeneity between study designs: Q=3.93, p=0.14. Figure 2(c). Meta-analysis of the risk of NHL associated with BMI 30–39.99 kg m⁻² (Grade 2 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=59.7, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=69.8%. For continents: North America: Q=8.18, p=0.08, I²=51.1%; Northern Europe: Q=18.1, p=0.01, I²=61.2%; Southern Europe: Q=7.88, p=0.05, I²=62.0%; Asia (Japan): Q=0.01, p=0.93, I²=0.0%. Test for heterogeneity between continents: Q=25.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=1.06, 95% CI 0.83–1.34, Q=41.3, p<0.001, I²=80.7%; Clinic-based studies: OR=1.22, 95% CI 0.90–1.67, Q=0.03, p=0.99, I²=0.0%; Hospital-based studies: OR=0.77, 95% CI 0.60–0.98, Q=8.51, p=0.20, I²=29.5%. Test for heterogeneity between study designs: Q=9.81, p=0.007. Figure 2(d). Meta-analysis of the risk of NHL associated with BMI ≥40 kg m⁻² (Grade 3 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=21.9, p=0.15; Variation in odds ratios (OR) attributable to heterogeneity: I²=26.8%. For continents: North America: Q=2.89, p=0.58, I²=0.0%; Northern Europe: Q=15.3, p=0.03, I²=54.4%; Southern Europe: Q=0.69, p=0.88, I²=0.0%. Test for heterogeneity between continents: Q=2.91, p=0.23. Pooled odds ratios by study design were: Population-based studies: OR=1.33, 95% CI 0.88–2.00, Q=11.4, p=0.18, I²=29.7%; Clinic-based studies: OR=0.57, 95% CI 0.26–1.22, No test for heterogeneity as only 1 study; Hospital-based studies: OR=0.51, 95% CI 0.25–1.05, Q=2.07, p=0.91, I²=0.0%. Test for heterogeneity between study designs: Q=8.41, p=0.015.

Figure 2

Figure 2(a). Meta-analysis of the risk of NHL associated with BMI <18.5 kg m⁻² (Underweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=13.0, p=0.73; Variation in odds ratios (OR) attributable to heterogeneity: I²= 0.0%. For continents: North America: Q=1.04, p=0.90, I²=0.0%; Northern Europe: Q=7.87, p=0.25, I²=23.7%; Southern Europe: Q=1.03, p=0.80, I²=0.0%; Asia (Japan): Q=1.38, p= 0.24, I²=27.5%. Test for heterogeneity between continents: Q=1.82, p=0.61. Pooled odds ratios by study design were: Population-based studies: OR=0.91, 95% CI 0.68–1.21, Q=6.75, p=0.56, I²=0.0%; Clinic-based studies: OR=0.92, 95% CI 0.65–1.31, Q=1.47, p=0.48, I²=0.0%; Hospital-based studies: OR=0.67, 95% CI 0.39–1.17, Q=3.79, p=0.58, I²=0.0%. Test for heterogeneity between study designs: Q=1.04, p=0.59. Figure 2(b). Meta-analysis of the risk of NHL associated with BMI 25–29.99 kg m⁻² (Grade 1 overweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=60.0, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=70.0%. For continents: North America: Q=2.76, p=0.60, I²=0.0%; Northern Europe: Q=25.0, p=0.001, I²=72.1%; Southern Europe: Q=8.59, p=0.04, I²=65.1%; Asia (Japan): Q=0.02, p=0.90, I²=0.0%. Test for heterogeneity between continents: Q=23.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=0.97, 95% CI 0.82–1.14, Q=41.6, p<0.001, I²=80.8%; Clinic-based studies: OR=0.99, 95% CI 0.82–1.20, Q=0.44, p=0.80, I²=0.0%; Hospital-based studies: OR=0.91, 95% CI 0.72–1.16, Q=14.0, p=0.03, I²=57.1%. Test for heterogeneity between study designs: Q=3.93, p=0.14. Figure 2(c). Meta-analysis of the risk of NHL associated with BMI 30–39.99 kg m⁻² (Grade 2 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=59.7, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=69.8%. For continents: North America: Q=8.18, p=0.08, I²=51.1%; Northern Europe: Q=18.1, p=0.01, I²=61.2%; Southern Europe: Q=7.88, p=0.05, I²=62.0%; Asia (Japan): Q=0.01, p=0.93, I²=0.0%. Test for heterogeneity between continents: Q=25.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=1.06, 95% CI 0.83–1.34, Q=41.3, p<0.001, I²=80.7%; Clinic-based studies: OR=1.22, 95% CI 0.90–1.67, Q=0.03, p=0.99, I²=0.0%; Hospital-based studies: OR=0.77, 95% CI 0.60–0.98, Q=8.51, p=0.20, I²=29.5%. Test for heterogeneity between study designs: Q=9.81, p=0.007. Figure 2(d). Meta-analysis of the risk of NHL associated with BMI ≥40 kg m⁻² (Grade 3 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=21.9, p=0.15; Variation in odds ratios (OR) attributable to heterogeneity: I²=26.8%. For continents: North America: Q=2.89, p=0.58, I²=0.0%; Northern Europe: Q=15.3, p=0.03, I²=54.4%; Southern Europe: Q=0.69, p=0.88, I²=0.0%. Test for heterogeneity between continents: Q=2.91, p=0.23. Pooled odds ratios by study design were: Population-based studies: OR=1.33, 95% CI 0.88–2.00, Q=11.4, p=0.18, I²=29.7%; Clinic-based studies: OR=0.57, 95% CI 0.26–1.22, No test for heterogeneity as only 1 study; Hospital-based studies: OR=0.51, 95% CI 0.25–1.05, Q=2.07, p=0.91, I²=0.0%. Test for heterogeneity between study designs: Q=8.41, p=0.015.

Figure 2

Figure 2(a). Meta-analysis of the risk of NHL associated with BMI <18.5 kg m⁻² (Underweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=13.0, p=0.73; Variation in odds ratios (OR) attributable to heterogeneity: I²= 0.0%. For continents: North America: Q=1.04, p=0.90, I²=0.0%; Northern Europe: Q=7.87, p=0.25, I²=23.7%; Southern Europe: Q=1.03, p=0.80, I²=0.0%; Asia (Japan): Q=1.38, p= 0.24, I²=27.5%. Test for heterogeneity between continents: Q=1.82, p=0.61. Pooled odds ratios by study design were: Population-based studies: OR=0.91, 95% CI 0.68–1.21, Q=6.75, p=0.56, I²=0.0%; Clinic-based studies: OR=0.92, 95% CI 0.65–1.31, Q=1.47, p=0.48, I²=0.0%; Hospital-based studies: OR=0.67, 95% CI 0.39–1.17, Q=3.79, p=0.58, I²=0.0%. Test for heterogeneity between study designs: Q=1.04, p=0.59. Figure 2(b). Meta-analysis of the risk of NHL associated with BMI 25–29.99 kg m⁻² (Grade 1 overweight) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=60.0, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=70.0%. For continents: North America: Q=2.76, p=0.60, I²=0.0%; Northern Europe: Q=25.0, p=0.001, I²=72.1%; Southern Europe: Q=8.59, p=0.04, I²=65.1%; Asia (Japan): Q=0.02, p=0.90, I²=0.0%. Test for heterogeneity between continents: Q=23.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=0.97, 95% CI 0.82–1.14, Q=41.6, p<0.001, I²=80.8%; Clinic-based studies: OR=0.99, 95% CI 0.82–1.20, Q=0.44, p=0.80, I²=0.0%; Hospital-based studies: OR=0.91, 95% CI 0.72–1.16, Q=14.0, p=0.03, I²=57.1%. Test for heterogeneity between study designs: Q=3.93, p=0.14. Figure 2(c). Meta-analysis of the risk of NHL associated with BMI 30–39.99 kg m⁻² (Grade 2 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=59.7, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=69.8%. For continents: North America: Q=8.18, p=0.08, I²=51.1%; Northern Europe: Q=18.1, p=0.01, I²=61.2%; Southern Europe: Q=7.88, p=0.05, I²=62.0%; Asia (Japan): Q=0.01, p=0.93, I²=0.0%. Test for heterogeneity between continents: Q=25.4, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=1.06, 95% CI 0.83–1.34, Q=41.3, p<0.001, I²=80.7%; Clinic-based studies: OR=1.22, 95% CI 0.90–1.67, Q=0.03, p=0.99, I²=0.0%; Hospital-based studies: OR=0.77, 95% CI 0.60–0.98, Q=8.51, p=0.20, I²=29.5%. Test for heterogeneity between study designs: Q=9.81, p=0.007. Figure 2(d). Meta-analysis of the risk of NHL associated with BMI ≥40 kg m⁻² (Grade 3 obese) compared to BMI 18.5–24.99 kg m⁻² (Normal weight). Overall test for heterogeneity: Q=21.9, p=0.15; Variation in odds ratios (OR) attributable to heterogeneity: I²=26.8%. For continents: North America: Q=2.89, p=0.58, I²=0.0%; Northern Europe: Q=15.3, p=0.03, I²=54.4%; Southern Europe: Q=0.69, p=0.88, I²=0.0%. Test for heterogeneity between continents: Q=2.91, p=0.23. Pooled odds ratios by study design were: Population-based studies: OR=1.33, 95% CI 0.88–2.00, Q=11.4, p=0.18, I²=29.7%; Clinic-based studies: OR=0.57, 95% CI 0.26–1.22, No test for heterogeneity as only 1 study; Hospital-based studies: OR=0.51, 95% CI 0.25–1.05, Q=2.07, p=0.91, I²=0.0%. Test for heterogeneity between study designs: Q=8.41, p=0.015.

Figure 3

Meta-analysis of the risk of NHL associated with 5 kg m⁻² increase in BMI above 18.5 kg m⁻² (Normal weight and above). Overall test for heterogeneity: Q=87.5, p<0.001; Variation in odds ratios (OR) attributable to heterogeneity: I²=79.4%. For continents: North America: Q=15.5, p=0.004, I²=74.1%; Northern Europe: Q=37.4, p<0.001, I²=81.3%; Southern Europe: Q=5.32; p=0.15; I²=43.6%; Asia (Japan): Q=0.12, p=0.73, I²=0.0%. Test for heterogeneity between continents: Q=29.0, p<0.001. Pooled odds ratios by study design were: Population-based studies: OR=1.02, 95% CI 0.92–1.13, Q=57.7, p<0.001, I²=86.1%; Clinic-based studies: OR=1.04, 95% CI 0.94–1.14, Q=0.34, p=0.84, I²=0.0%; Hospital-based studies: OR=0.85, 95% CI 0.79–0.92, Q=6.09, p=0.41, I²=1.4%. Test for heterogeneity between study designs: Q=23.4, p<0.001.

Figure 4

Comparison of Control and WHO Overweight/Obesity Prevalences by Study. Overweight (BMI 25–29.99 kg m⁻²) and Obesity (BMI ≥ 30 kg m⁻²) prevalence from the World Health Organisation (WHO) Global Database on Body Mass Index (http://www.who.int/bmi/). WHO prevalence was derived from the most recent published age- and sex- standardised BMI data calculated from height and weight measured in clearly defined population samples; these data were largely from around the year 2000. The relative order of control overweight/obesity prevalences across studies was not similar to that from data reported on the WHO Global database for BMI (Spearman’s ρ=0.41, p=0.08).