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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 213-218
Copyright © 2004 by The Endocrine Society

Do Height-Related Variations in Insulin-Like Growth Factors Underlie the Associations of Stature with Adult Chronic Disease?

D. Gunnell, S. E. Oliver, J. L. Donovan, T. J. Peters, D. Gillatt, R. Persad, F. C. Hamdy, D. E. Neal and J. M. P. Holly

Department of Social Medicine (D.G., J.L.D.), University of Bristol, Bristol BS8 2PR; Department of Health Sciences (S.E.O.), University of York and Hull York Medical School, York YO10 5DD; Division of Primary Health Care (T.J.P.), University of Bristol, Bristol BS6 6JL; Division of Surgery (D.G., R.P., J.M.P.H.), University of Bristol, Bristol BS2 8HW; Academic Urology Unit (F.C.H.), University of Sheffield, Sheffield S10 2JF; and Oncology Centre (D.E.N.), Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: David Gunnell, Senior Lecturer in Epidemiology and Public Health Medicine, Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, United Kingdom. E-mail: D.J.Gunnell{at}bristol.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusions
 References
 
Tall people, particularly those with long legs, have an increased risk of developing cancer but a reduced risk of cardiovascular disease and type II diabetes. We examined associations of stature and body mass index with IGF-I, IGF-II, and IGF binding protein (IGFBP)-2 and IGFBP-3 in 274 men aged 50–70 yr to investigate whether variations in growth factor levels underlie associations of anthropometry with a number of adult diseases. Height and leg and trunk length were not strongly associated with circulating levels of IGF-I, IGF-II, or IGFBP-3. The molar ratio of IGF-I/IGFBP-3 increased with increases in the leg/trunk length ratio (P = 0.06). IGFBP-2 was positively associated with leg length and inversely associated with trunk length. Mean levels of IGFBP-2 (in nanograms per milliliter) across quartiles of increasing leg length were 504.4 493.6, 528.7, and 578.8 (Ptrend = 0.06), and for trunk length were 615.2, 507.2, 498.6, 488.5 (Ptrend < 0.01), suggesting that variations in IGFBP-2, or a factor influencing its levels in the circulation, may contribute to biological mechanisms underlying height-disease associations. We conclude that whereas growth-influencing exposures during childhood, which may operate through effects on IGF-I levels, have long-term influences on disease risk, they do not necessarily program IGF-I levels throughout life. The associations of anthropometry with IGFBP-2 merit additional investigation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 Conclusions
 References
 
MANY EPIDEMIOLOGICAL STUDIES have reported that tall individuals are at an increased risk of a range of different cancers, particularly breast, prostate, colorectal, endometrial, and hematopoietic malignancies (1). In contrast, height is inversely associated with cardiovascular disease (2) and cardiovascular risk factors, such as insulin resistance (3). A series of recent studies indicate that leg length is the component of height most strongly associated with cancer and cardiovascular disease (3, 4, 5). As growth in infancy and childhood before puberty is in greater part due to increases in leg length than trunk length (6), it has been suggested that associations of adult disease with stature may indicate the long-term influence of growth-altering exposures in childhood, such as diet and infection, on adult health (7).

In childhood, the GH-IGF axis plays an important role in controlling growth. Levels of IGF-I are strongly associated with childhood height (8, 9), and for this reason it has been speculated that the high levels of IGF-I in tall adults may underlie the height-disease associations. This speculation is supported by a series of recent studies linking the IGF axis, particularly raised levels of IGF-I and/or reduced levels of its main binding protein, IGFBP-3, with cancers of the breast, prostate, colorectum, and lung (10, 11). In contrast, raised levels of IGF-I are associated with a reduced risk of impaired glucose tolerance (12), favorable levels of cardiovascular disease risk factors (13), and a lower incidence of coronary heart disease (14). The role of IGF-II and IGFBP-2 in postnatal growth and their associations with cancer and cardiovascular disease are less clear-cut. IGF-II has been shown to be positively associated with risk of prostate (15) and colorectal cancer (16) in some studies. IGFBP-2 is the second most abundant IGFBP in the circulation and is generally considered to be a growth inhibitor. Its association with cancer is unclear; prospective studies report no association with prostate cancer (17) but an inverse relationship with breast cancer (18). Raised levels are thought to be associated with colorectal and prostate cancer progression (19, 20, 21, 22).

In addition to the relationship of linear growth with adult cardiovascular disease and cancer already described, a number of studies also report adverse associations of adiposity with these disorders (2, 23, 24). Studies examining the association of IGF-I and IGFBP-3 levels with body mass index (BMI) have generally found no strong evidence of an association (25, 26, 27). In contrast, an analysis of premenopausal Dutch women indicated that those with raised BMI had lower levels of IGFBP-1 and -2 and raised levels of IGFBP-3 (28).

Although a number of previous investigations have examined associations between IGF-I and adult height with mixed results (29, 30, 31, 32, 33), to the best of our knowledge, none have examined the IGF axis in relation to the main components of adult height, leg length and trunk length. We have investigated associations of the IGF axis with adult height, the components of height, and BMI in a group of disease-free men who were controls in a population-based case-control study of screen-detected prostate cancer. Our aim was to determine whether variations in growth factor levels in relation to height, leg length, and BMI underlie the associations of these anthropometric variables with cancer, insulin resistance, and coronary heart disease.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 Conclusions
 References
 
As part of a nested case-control study examining the association of prostate cancer with IGF-I, IGF-II, IGFBP-2, and IGFBP-3, the stored blood samples of 368 disease-free men aged 50–70 (controls) were assayed for IGF-I, IGF-II, IGFBP-2, and IGFBP-3 (15). Two hundred and seventy-four (74%) of these men had had height measurements recorded, and they form the basis of this analysis. The study men were drawn from among 7383 participants recruited in the early stages of a large population-based study into the detection and treatment of prostate cancer, the ProtecT study (34). The men were registered with 18 general practices in Bristol, Newcastle, and Sheffield and provided blood samples for prostate-specific antigen testing at clinics held between August 1999 and July 2001.

The measurements of height, sitting height, and weight were made at the clinics by trained nurses using standardized procedures. All men were also asked to complete a health and lifestyle questionnaire that elicited information on occupation, smoking, and physical activity. Height and sitting height were measured using a Leicester portable stadiometer. Weight was measured to the nearest 100 g using Seca electronic scales. Subjects were asked to remove their shoes and overcoats and remove heavy items from their pockets before measurement. Leg length was calculated as the difference between overall height and sitting height, less the height of the measuring stool used for the sitting height measurements. Trunk length was calculated as the difference between leg length and total height. BMI, a measure of adiposity, was calculated as weight (in kilograms) divided by height (in meters) squared (kilograms per meter2). The main reason for missing anthropometric measures among the original 368 control men was time constraints in the clinic. Men who did and those who did not have height measurements did not differ significantly with respect to their mean levels of IGF-I, IGF-II, IGFBP-2, or IGFBP-3

IGF measurements

Nonfasted blood specimens were taken using standard techniques, and samples were stored in a cool-box or fridge at 5 C until transferred to a laboratory for processing. Blood specimens were spun and frozen to -80 C within 18 h. Assays were carried out in Professor Holly’s laboratory, Bristol. Double-antibody ELISAs were used to measure IGF-I (Diagnostic Systems Laboratories, Webster, TX; DSL-10–2800 ACTIVE) and IGF-II (Diagnostic Systems Laboratories; DSL-10–2600). Total levels of IGFBP-2 were measured by RIA (Diagnostic Systems Laboratories; DSL-7100). Assays for serum IGFBP-3 used a previously validated in-house double-antibody RIA (35). Results for IGF-I concentration were based on the average of two measures and for IGFBP-3 on the average of three measures.

It has been suggested that the ratio of IGF-I to its principle binding protein IGFBP-3 provides a measure of biologically active IGF-I. Based on the molecular weight of IGF-I (7500) and IGFBP-3 (40,000, mean of glycosylated variants) we calculated the molar ratio of IGF-I/IGFBP-3 by multiplying the ratio by 5.33 (40,000/7,500). The average coefficients of variation for intraassay variability for IGF-I, IGF-II, IGFBP-3, and IGFBP-2 were 3, 5, 4, and 5% and for interassay variation were 15, 26, 14, and 14%.

Statistical analysis

All data analyses were performed using Intercooled Stata 7.0 for Windows 2001 (Stata Corp., College Station, TX). For the analysis of mean growth factor levels across quartiles of the anthropometric measures, we calculated age- and center-adjusted levels of the growth factors and their binding proteins.

To assess confounding, we contrasted the regression coefficients per SD change in the anthropometric variables in 1) simple models controlling for age and study center only with those in 2) models including terms for BMI (as a continuous variable), smoking (as three categories never, ex-smokers, and current smokers), social class (four groups using the Registrar General’s classification: I, II, III, and IV/V), and levels of exercise (coded into three groups based on weighted levels of strenuous, moderate, and light activity) (36). Tests for trends in these models are based on each variable fitted as a continuous term in the models.

The distributions of IGFBP-2 and the molar ratio IGF-I/IGFBP-3 were positively skewed. We therefore report geometric means of their values across quartiles of the anthropometry. Models of the association of IGFBP-2 and the molar ratio IGF-I/IGFBP-3 with z-scores for height, leg length, trunk length, and the leg/trunk ratio are based on the log-transformed values of the growth factors.

As the men (controls) had been matched to cases on the basis of their age (2-yr age bands), the general practice of the case, and date of recruitment (closest date) (15), weights were applied to regression analyses reflecting the inverse probability of sampling by age group.

Ethical approval

Ethical approval for the study was obtained from South and West Multicenter Research Ethics Committee and the relevant Local Ethics Committees in the study centers.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 Conclusions
 References
 
Table 1Go shows the characteristics of the 274 men who formed the basis of this analysis. Their mean age was 62 yr. Table 2Go shows the correlations between the various measures of stature and the IGF axis. Leg length and trunk length were weakly correlated (r = 0.29), indicating their values are relatively independent of one another. IGF-I and -II were not strongly related to any of the measures of height. IGF-I and -II were strongly associated with levels of IGFBP-3 (r = 0.44 and 0.56, respectively) but were only weakly, and inversely, associated with IGFBP-2 (r = –0.13 and –0.12, respectively). Men with high levels of IGFBP-2 tended to have low levels of IGFBP-3 (r = –0.23). The factor most strongly related to the anthropometric measures was IGFBP-2; circulating levels were inversely related to trunk length (r = -0.17) and BMI (r = –0.44) and positively associated with the leg:trunk ratio (r = 0.18).


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  		TABLE 1. Characteristics of study men

 

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  		TABLE 2. Pearsons’s correlations between measures of stature and growth factor levels (n = 263 with all measures)

 
Age- and center-adjusted mean and geometric means (IGFBP-2 and molar ratio IGF-I/BP-3) of the serum growth factor measures across quartiles of anthropometry are shown in Table 3Go. No associations are seen with IGF-I. There was a weak positive association of IGF-II with height, which was mainly due to the trunk component of stature. Although circulating levels of IGFBP-2 were unrelated to height, they were positively associated with leg length (P = 0.06) and leg:trunk ratio (P < 0.01) and inversely related to trunk length (P = 0.01) and BMI (P < 0.001). There was a borderline positive association between the molar ratio IGF-I/IGF-BP-3 and the leg:trunk ratio; those who had longer legs relative to their trunks had higher levels of the IGF-I/IGFBP-3 molar ratio (P = 0.06).


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  		TABLE 3. Levels of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 ratio in relation to quarfiles of height, leg length, trunk length, leg/trunk ratio, and BMI

 
Table 4GoGo gives the regression coefficients from models to assess possible confounding by smoking, exercise, and social class based on the 249 study members with complete data for these variables. The association of trunk length with IGFBP-2 and similarly, therefore, the association of the leg:trunk ratio with IGFBP-2 were attenuated in the fully adjusted models. The factor that accounted for most of this attenuation was BMI, which itself was associated with both IGFBP-2 and trunk length (see Table 2Go). Associations of leg length with IGFBP-2 and of the molar ratio with the leg:trunk ratio were only slightly attenuated in the fully adjusted models.


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  		TABLE 4. Change in measure of the IGF axis (95% CI) per SD change in height, leg length, trunk length, leg:trunk ratio, and BMI

 

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  		TABLE 4A. Continued

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
Conclusions
 References
 
Circulating levels of IGFBP-2 were inversely associated with trunk length and BMI and positively associated with leg length and the leg:trunk ratio. The relationships of IGFBP-2 with trunk length and the leg:trunk ratio were partially explained by the inverse association of IGFBP-2 with BMI, which in turn is associated with trunk length. Leg length associations with IGFBP-2 were little affected in models controlling for BMI. Contrary to our predictions, we found no evidence of an association of IGF-I with height or leg length. Nevertheless, the molar ratio of IGF-I/IGFBP-3, which provides an indication of bioavailable IGF-I, was weakly positively associated with the leg:trunk ratio, an indicator of relatively long leg length in relation to total stature. Of the two components of stature, trunk length rather than leg length was positively associated with IGF-II. Our study therefore provides limited evidence that differences in body proportions (leg:trunk ratios) in adulthood may act as indicators of bioavailable IGF-I and this may be the biological mechanism linking stature to adult chronic disease risk.

Biological role of IGFBP-2

The physiological role of IGFBP-2 is less well characterized than that of IGF’s main binding protein, IGFBP-3. The fact that IGFBP-2 forms only low molecular weight binary complexes with IGFs, in contrast to the large ternary complexes formed with IGFBP-3, means that it is able to traverse capillary walls making growth factors available to tissues to a greater extent than does IGFBP-3. In healthy individuals, circulating levels of IGFBP-2 are inversely related to IGF-I and IGFBP-3 (28, 30). In keeping with this, we found the correlations of these factors with IGFBP-2 were –0.13 and –0.23, respectively, indicating it has a different physiological role from that of IGFBP-3. Like IGFBP-3, levels of IGFBP-2 show little diurnal variation and, unlike IGFBP-1, its levels do not vary in response to meals or glucose infusions (37). Levels of IGFBP-2 remain relatively stable throughout childhood (30, 38) and, in keeping with our findings, two studies in healthy females report that BMI was strongly inversely related to IGFBP-2 but unrelated to height (28, 29).

IGFBP-2 and adult disease

Few studies investigating the relationship of IGFs with cancer and cardiovascular disease have examined their associations with IGFBP-2. Raised levels of IGFBP-2 have been reported in case control studies of prostate and colorectal cancer, using blood samples taken at the time of diagnosis (20, 21, 22). Higher levels are found in those with more advanced disease, and one study of colorectal cancer found that levels declined after tumor resection (22). These findings indicate that IGFBP-2 is produced by tumors, rather than being of importance in their causation, a suggestion supported by the one prospective study examining its association with prostate cancer, which found no evidence of increased levels in men several years before diagnosis (17). However, a recently published prospective study of breast cancer risk reported considerably reduced risk of postmenopausal breast cancer among women in the top quartile of IGFBP-2 levels, a finding more in keeping for those of IGFBP-3 and cancer risk. For these reasons, the associations of anthropometry with IGFBP-2 observed in the present study may not be important in explaining the associations of these anthropometric measures with cancer incidence.

Raised levels of IGFBP-2 are associated with chronic insulin deficiency caused, for example, by insulin-dependent diabetes or GH deficiency before replacement therapy (37, 39). Furthermore, in community-sampled healthy adult women, Kaaks et al. (40) reported inverse associations between IGFBP-2 and circulating insulin levels (r = -0.31). A similar association (r = -0.28) has been reported in elderly males (41). It is possible, therefore, that low levels of IGFBP-2 may occur in conditions of insulin excess, such as the insulin resistance syndrome. If this were the case, our findings of raised levels of IGFBP-2 in those with longer legs and shorter trunks would be in keeping with other epidemiological studies reporting that short leg length and overweight (i.e. low IGFBP-2 and raised insulin) are associated with insulin resistance and coronary heart disease (2, 4).

Alternative explanations for observed associations

As this is a cross-sectional study, we cannot rule out the possibility that the associations we observed arose as a result of the effects of the growth factor axis on height loss in middle old age (reverse causality). There is some evidence that osteoporosis is associated with lower levels of IGF-I (42) and osteoporotic height loss in old age is more due to loss of trunk length, as a result of vertebral collapse, than loss of long bone (leg) length (43). The associations we observed could therefore reflect the effect of growth factors on age-associated changes in bone structure rather than reflecting the effects of factors influencing childhood growth on growth factor levels. A study of stature-growth factor associations in younger people would clarify these issues.

We have examined associations with a range of anthropometric variables and five different measures of the IGF axis. Such multiple hypothesis testing increases the likelihood of chance findings. As the analysis was limited to older men, the findings cannot necessarily be extrapolated to women or younger people. Studies in children, however, demonstrate strong associations between IGF-I levels and both stature and weight in childhood (8, 9), but such associations may be due to the role of IGF-I in influencing growth velocity rather than final adult height and may not persist, or be weaker, in adulthood.


   Conclusions
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusions
References
 
The strong associations of body proportions and BMI with IGFBP-2 require additional investigation. Associations between anthropometric measures and adult diseases are not reflected strongly by associations between IGF-I and IGFBP-3 measures and anthropometry. This could be because adult height and leg length are determined by factors, including IGFs, during childhood growth that, because of the range of other influences on circulating IGFs (44, 45), are less strongly associated with adult anthropometry. The associations between anthropometric measures and adult disease therefore suggests that growth-influencing exposures during childhood, which may act through the GH-IGF axis, may have long-term influences on disease risk but do not necessarily program IGF levels throughout life.


   Acknowledgments
 
We acknowledge Sara Bright, Zoe Wilkins, Tracey Calthorpe, and Andrea Wilson for providing clerical support; Mark Sidaway and Daniel Dedman for database management; research Nurses Peter Holding, Teresa Mewes, Sally Burton, Liz Salter, Louise Goodwin, Ingrid Emmerson, Miranda Benney, Sue Kilner, Lyn Wilkinson, Clare Kennedy, Christine Hardy, and Andrew Robinson; and Anya Pearce for performing the IGF assays.


   Footnotes
 
This work was supported by National Health Service (NHS) South and West Research and Development. The ProtecT study is funded by the NHS Health Technology Assessment Program.

Abbreviations: BMI, Body mass index; IGFBP, IGF binding protein.

Received March 24, 2003.

Accepted October 13, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusions
 References
 

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