Relation of Height and Body Mass Index to Renal Cell Carcinoma in Two Million Norwegian Men and Women

Tone Bjørge1, Steinar Tretli2 and Anders Engeland3 

1 Department of Pathology, Norwegian Radium Hospital, Oslo, Norway.
2 Cancer Registry of Norway, Institute of Population-based Cancer Research, Oslo, Norway.
3 Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.

Received for publication July 3, 2004; accepted for publication September 16, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A positive association between body mass index (BMI) and renal cell carcinoma (RCC) has been observed. The association between height and RCC has been less clear. The authors explored these relations in a very large Norwegian cohort. Height and weight were measured in two million Norwegian men and women aged 20–74 years during 1963–2001. During follow-up, 6,453 cases of RCC were registered in the national cancer database. Measurements were also performed in 227,000 adolescents aged 14–19 years, and 154 cases of RCC were registered. Relative risks for RCC were estimated using Cox proportional hazards regression. The risk of RCC increased with increasing BMI among both adults and adolescents. Among adults, the relative risk associated with a one-unit increase in BMI was 1.05 (95% confidence interval (CI): 1.04, 1.06) in both sexes. The relative risk associated with a 10-cm increase in height was 1.19 (95% CI: 1.13, 1.26) in men and 1.17 (95% CI: 1.09, 1.26) in women. In a subgroup analysis, the relation between BMI and RCC was most pronounced in men and women who were never smokers, and the relation between height and RCC was confined to ever smokers. The authors conclude that elevated BMIs are associated with RCC risk in both males and females across a wide age range.

body height; body mass index; carcinoma, renal cell; kidney neoplasms

Abbreviations: Abbreviations: BMI, body mass index; CI, confidence interval; RCC, renal cell carcinoma.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Overweight or obesity has been linked to increased risk of total mortality (1) and to increased risk of death from several site-specific cancers (2), including kidney cancer. It is estimated that in the year 2000, kidney cancer was responsible for 1.9 percent of new cancer cases and 1.5 percent of cancer deaths worldwide (3). The incidence of kidney cancer is highest in North America and Europe (4). In 2000, the age-adjusted (world standard population) incidence of kidney cancer, excluding the renal pelvis, was 8 per 100,000 person-years and 4 per 100,000 person-years in men and women, respectively, and constituted 2.5 percent and 1.6 percent of the (age-adjusted) cancer incidence in Norway (5).

Most kidney cancers (~80 percent) are renal cell carcinomas (RCCs) (6). Cigarette smoking is an established causal factor for the development of RCC (7). Obesity has also been suggested to be a risk factor for RCC, and a number of studies, mostly case-control studies, have explored this relation (7, 8). The relation between obesity and RCC has been most pronounced in women (7, 9, 10). However, a recent review found a positive relation between body mass index (BMI) and RCC that was equally strong for both sexes (8). High blood pressure or use of medication for hypertension may also play a role, although the mechanism is unknown (7). Age and smoking have been considered to be the most important confounding factors in the relation between obesity and RCC (8). Few studies have explored the association between height and risk of RCC, and the results have been inconsistent (11).

Our aim in the present study was to explore the associations between height and BMI and the risk of RCC in a very large Norwegian cohort of both men and women with a long follow-up period.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We have previously described the study population and the methods used in the present study (1214). Here we give a brief description only.

Study population
In a number of health surveys carried out during the period 1963–2001, height and weight were measured in a standardized way by a trained staff among 2,001,719 persons (963,709 men and 1,038,010 women) aged 20–74 years (the "adult cohort"). In a tuberculosis screening program conducted in 1963–1975, height and weight were measured in 227,224 young people (115,270 boys and 111,954 girls) aged 14–19 years (the "adolescent cohort"). Some persons were included in both cohorts. Consequently, the total number of study subjects was 2,089,182.

Deaths, emigrations, and cases of kidney cancer (International Classification of Diseases, Seventh Revision, code 180) observed in these cohorts were identified by linkage to the Death Registry at Statistics Norway (15) and to the Cancer Registry of Norway (5). The two registries are population-based and cover the entire Norwegian population. A unique 11-digit identification number assigned to all persons living in Norway after 1960 simplified the linkage process.

In the present study, only histologically verified diagnoses of RCC were included. Persons who received a diagnosis of RCC prior to the measurement of height and weight were excluded (409 persons in the adult cohort). In the analyses, the subjects were followed from the date of measurement to the date of RCC diagnosis, emigration, age 100 years, or death or until December 31, 2002. Altogether, 2,001,310 persons (963,485 men and 1,037,825 women) were eligible for study in the adult cohort. A very small number of these subjects (43 men and 37 women) were lost to follow-up. In the adolescent cohort, only three boys out of 227,224 boys and girls were lost to follow-up.

Some of the health surveys carried out during 1972–2001 included questions about smoking habits (self-administered questionnaire). A subanalysis was performed including only those who had answered questions on smoking habits. The study subjects were divided into never, former, and current smokers. Information on smoking habits was available for 647,093 persons (322,746 men and 324,347 women) included in the adult cohort, after exclusions. The subanalysis was performed with the same exclusion criteria and follow-up procedure as the main analysis.

Statistical methods
Cox proportional hazards regression models (16) with time since height and weight measurement used as the time variable were fitted to obtain relative risk estimates for RCC. In the analyses, categorized variables for age at measurement, year of birth, BMI (weight (kg)/height (m)2), and height were included. In the adult cohort, BMI was categorized using the World Health Organization categorization (17): <18.5, underweight; 18.5–24.9, normal; 25.0–29.9, pre-obese/overweight; and ≥30.0, obese. In the adolescent cohort, BMI was categorized using growth percentiles (low, <25th; medium, 25th–74th; high, 75th–84th; very high, ≥85th) from a US reference population, following the guidelines of the Centers for Disease Control and Prevention and the National Center for Health Statistics (18, 19).

We performed tests for trend in the risk of RCC by BMI and height by conducting analyses including BMI and height, respectively, as continuous variables. To explore whether BMI had a differential impact on the incidence of RCC for different age groups, we performed analyses stratified on both age at measurement and attained age. These analyses did not add information to the main analysis.

All of the above-mentioned analyses were performed with the statistical software package SPSS (20). The results are presented as relative risks and 95 percent confidence intervals. The hazard function for RCC by BMI in the Cox model was estimated using penalized spline functions in S-Plus (21), with 4 degrees of freedom.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adult cohort
The 2,001,230 persons (963,442 men and 1,037,788 women) included in the present study were followed for an average of 23 years (range, 0–40 years), which constituted 45.7 million person-years of follow-up (table 1). The mean age at measurement was 44 years. During follow-up, 6,453 cases of RCC were diagnosed among the study subjects. The mean age at diagnosis was 66 years, and measurements were made an average of 18 years prior to diagnosis. More than twice-as-large proportions of both underweight and obesity were observed in women as in men. The proportions of underweight were 0.7 percent and 2.0 percent in men and women, respectively, while the proportions of obesity were 6 percent and 13 percent.


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TABLE 1. Numbers of observed cases of renal cell carcinoma (RCC), person-years of follow-up, and overall rates of RCC among persons aged 20–74 years at study entry, Norway, 1963–2001
 
An increase in RCC risk was seen in both sexes with increasing BMI and height (table 2). Adjusting the BMI results for height and vice versa did not change the results. The relative risk associated with a one-unit increase in BMI was 1.05 (95 percent confidence interval (CI): 1.04, 1.06) in both sexes. For a person with a height of 176 cm, a one-unit increase in BMI is 3 kg. Splitting the upper BMI category gave us relative risks of 1.89 (95 percent CI: 1.22, 2.94) and 2.76 (95 percent CI: 0.89, 8.56) among men with BMIs of 35–39 and ≥40, respectively, compared with men of normal weight. The corresponding figures for women were 2.13 (95 percent CI: 1.75, 2.60) and 2.59 (95 percent CI: 1.81, 3.70). The proportions of persons with BMIs of 35–39 and ≥40 were 0.5 percent and 0.1 percent, respectively, in men and 2.4 percent and 0.6 percent, respectively, in women. The mean BMIs in these categories were 37 and 43, respectively, in both sexes.


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TABLE 2. Relative risk of renal cell carcinoma in Cox regression analyses among persons aged 20–74 years at study entry, Norway, 1963–2001*
 
In stratified analyses separating persons born before 1930 from persons born in 1930 or later, we observed a somewhat higher increase in the relative risk of RCC by increasing BMI in persons born from 1930 onwards than in persons born before 1930.

The relative risk associated with a 10-cm increase in height was 1.19 (95 percent CI: 1.13, 1.26) in men and 1.17 (95 percent CI: 1.09, 1.26) in women. The estimated relative risks increased monotonically by increasing height across the height categories. The relative risk in tall (180–189 cm) versus short (150–159 cm) men was 1.86 (95 percent CI: 1.18, 2.93). The relative risk in tall (170–179 cm) versus short (140–149 cm) women was 2.21 (95 percent CI: 1.49, 3.29).

To exclude the possibility that, at the time of BMI measurement, weight was influenced by the presence of undiagnosed RCC, we analyzed the data after omitting the first 5 years of follow-up. The number of cases was reduced by 600, but similar results were found. That is, the largest change was that the relative risk in obese women changed from 1.85 (95 percent CI: 1.66, 2.06) to 1.92 (95 percent CI: 1.71, 2.14).

The association between BMI and RCC was also explored in detail using penalized spline functions (figure 1). The incidence of RCC increased steadily with BMI in both sexes.



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FIGURE 1. Log relative risk of renal cell carcinoma from penalized spline functions (4 df) among persons aged 20–74 years at study entry, according to body mass index, Norway, 1963–2001. Results were adjusted for birth cohort and age at height and weight measurement. Dashed lines, 95% confidence interval.

 
In the subcohort with known smoking habits, we performed an analysis similar to that shown in table 2, including 7,816,818 person-years (mean follow-up of 12 years). The mean age at measurement in the subcohort was 42 years. Compared with the entire cohort, the persons in the subcohort were from younger birth cohorts. About 50 percent of the entire cohort and about 90 percent of the subcohort was born in 1930 or later. In the subcohort, a total of 530 histologically verified cases of RCC were diagnosed in men and 251 in women. Mean ages at diagnosis were 58 years and 59 years in men and women, respectively. Similar results were obtained in analysis including this subcohort only (table 3) as in the main analysis. The number of cases in the lowest categories of BMI and height were very low (one and three cases in the lowest category of BMI in men and women, respectively, and two cases and one case in the lowest height category).


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TABLE 3. Relative risk of renal cell carcinoma in Cox regression analyses in a subcohort of participants with known smoking habits among persons aged 20–74 years at study entry, Norway, 1972–2001*
 
Including the three-category smoking variable did not change the estimates in the subcohort. However, stratified analyses in never, former, and current smokers revealed a somewhat more pronounced increase in the risk of RCC with increasing BMI in never smokers than in former or current smokers (table 3). The functions for risk of RCC by BMI among never smokers in the subcohort are shown in figure 2. The increasing risk of RCC with increasing height seemed to be confined to former or current smokers.



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FIGURE 2. Log relative risk of renal cell carcinoma from penalized spline functions (4 df) among never smokers aged 20–74 years at study entry (in a subcohort of persons with known smoking habits), according to body mass index, Norway, 1972–2001. Results were adjusted for birth cohort and age at height and weight measurement. Dashed lines, 95% confidence interval.

 
Adolescent cohort
The 227,221 adolescents (115,267 boys and 111,954 girls) included in the present study were followed for an average of 33 years (range, 0–40 years), constituting 7.5 million person-years of follow-up. The mean age at measurement was 17 years. During follow-up, 154 RCC cases were diagnosed among the study subjects. The mean age at diagnosis was 45 years, and measurements were made, on average, 28 years prior to diagnosis. The proportions of low BMI were 24 percent and 16 percent in boys and girls, respectively, while the proportions of high and very high BMI were 8 percent and 5 percent, respectively, in boys and 11 percent and 8 percent in girls.

An increase in risk was seen with increasing BMI in both sexes, especially in boys (table 4).


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TABLE 4. Relative risk of renal cell carcinoma in Cox regression analyses among persons aged 14–19 years at study entry, Norway, 1963–2001*
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this study, a Norwegian cohort of more than two million persons was followed prospectively with regard to RCC risk for an average of 23 years. More than 6,500 carcinomas were observed, and the risk of RCC increased with both BMI and height in both sexes. The risk of RCC increased with both BMI in adulthood and BMI in adolescence. Restricting the analysis to never smokers in a subcohort changed the results somewhat. Never smokers had the largest increase in risk of RCC with BMI. The positive relation between height and RCC was confined to ever smokers.

BMI is a simple and commonly used measure of body mass relative to height. However, BMI does not distinguish between weight associated with muscles and weight associated with fat (17). Although BMI is a crude indicator for percentage of body fat, there is generally very good correlation between BMI and the percentage of body fat in large populations (22). The categorization used in the present study (17) is recommended by the World Health Organization. The categorization is independent of age and is the same for both sexes. Nevertheless, the percentage of body fat mass is different for persons of different ages and different between the sexes. Hence, one should interpret results from studies including persons within a large age range, like the present one, with caution. We conducted separate analyses for men and women and for intervals of attained age and age at measurement. These analyses did not indicate that the crude impression from the main analyses, which were adjusted for age at measurement, was wrong. In addition, total mortality in the present cohort showed the same overall pattern by BMI across age groups (23).

In the review by Bergström et al. (8), the largest study was a population-based case-control study including 1,700 RCC cases (24). The majority of the studies included were case-control studies that relied on retrospective self-reporting of weight and height. One of the largest cohort studies on this topic (25) included 759 RCCs diagnosed in 360,000 men. In the present study, we could rely on standardized weight and height measurements taken in two cohorts, one with two million men and women measured at ages 20–74 years and one with 227,000 persons measured in adolescence. The measurements were performed a long time before diagnosis. More than 6,500 RCC cases were diagnosed in these cohorts during follow-up. In a subcohort with known smoking habits, 768 RCC cases occurred. Subsequently, the diagnoses in our study were ascertained through a population-based cancer registry, and the measurements and diagnoses were linked using a personal identification number.

Bergström et al. (8) calculated a summary relative risk of RCC per one-unit increase in BMI of 1.07 (95 percent CI: 1.05, 1.09). They noted that studies controlling for smoking revealed a slightly higher relative risk than studies that did not control for smoking. In the present study, not controlling for smoking, we found a relative risk of 1.05 (95 percent CI: 1.04, 1.06) per one-unit increase in BMI in both sexes. Estimation of fluctuations in the hazard of RCC by BMI using spline curves indicated that there was no threshold value in the association between BMI and RCC. The risk of RCC increased steadily with increasing BMI. In the subcohort with known smoking habits, adjustment for smoking habits did not change these relations. However, we observed that the relation between BMI and risk of RCC was stronger for never smokers than for ever smokers: Relative risks were 1.09 (95 percent CI: 1.03, 1.15) and 1.07 (95 percent CI: 1.03, 1.11) in male and female never smokers, respectively. Since smoking increases the risk of RCC and is inversely related to BMI, this effect was expected (8). A slightly stronger association between kidney cancer and BMI in never smokers than in former and current smokers was recently observed in a large population-based case-control study (26). The association between BMI and risk of RCC may be explained through several hormonal mechanisms (8, 9).

Earlier studies found a stronger association between obesity and RCC risk in women than in men. Gender-specific fat distributions and hormone levels might explain some of the difference (22). However, the stronger association observed in women might be partly explained by the present findings of a stronger relation between BMI and RCC risk in never smokers than in ever smokers. Previously, a larger proportion of women than of men were never smokers. On the contrary, Bergström et al. (8) suggested that the sex difference found in some studies might be explained by the differences in the distribution of BMIs among men and women within broad categories.

Reported results on the association between height and RCC have been inconsistent (11). However, the studies reviewed by Gunnell et al. (11), mainly case-control studies, were relatively small. One (27) of the two cohort studies included in the review found an increasing risk by height. Tulinius et al. (27) found that the relative risk associated with a 1-cm increase in height was 1.05 (95 percent CI: 1.02, 1.08) in men. In a more recent, large cohort study of Swedish men, no association between height and RCC was observed (25). In the present study, we found a slightly lower increase in risk per 1-cm increase in height (for both sexes, relative risk = 1.02, 95 percent CI: 1.01, 1.02) than did Tulinius et al. when smoking habits were not taken into consideration. However, we found an increased risk by height in both sexes. Moreover, because of our large study size, we were able to examine the risk in categories of height. We found a monotonically increasing risk by increasing height in both sexes. The tallest men and women had about twice the risk of the shortest men and women. This relation may pertain to genes or early-life exposures (11).

In a subanalysis, it seemed that the association between height and RCC was confined to ever smokers. If this is a true relation, this may explain the inconsistent findings on the relation between height and risk of RCC; the proportion of smokers differs between populations. However, this was not an expected finding, and it should be replicated by other investigators before firm conclusions are drawn.

In this study, we observed a positive association between BMI in adolescence and risk of RCC. However, we did not have enough persons with measurements taken in both adolescence and adulthood to explore whether this association was due to BMI in adolescence or BMI in adulthood. Since high BMI in adolescence is predictive for high BMI in adulthood (28), possible effects of these two factors on the risk of RCC are difficult to separate. Persons with an already-high BMI at the age of 20 years who gained further weight between the ages of 20 and 50 years were previously reported to have an increased risk of RCC (29).

In summary, in this large Norwegian cohort, the risk of RCC increased with BMI for both sexes, being most pronounced in never smokers. The positive association between BMI and risk of RCC was also observed in persons with measurements taken in adolescence. In addition, we found an increasing risk of RCC by increasing height that seemed to be confined to ever smokers.


    ACKNOWLEDGMENTS
 
The authors are grateful to all those who, over a period of almost 40 years, collected the data used in the present study. These persons were affiliated with the former National Health Screening Service, the Nord-Trøndelag Health Survey (HUNT), the Hordaland Health Survey (HUSK), and the Tromsø Study.


    NOTES
 
Correspondence to Dr. Anders Engeland, Division of Epidemiology, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway (e-mail: anders.engeland{at}fhi.no). Back


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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