© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 24, 2009-2017,
December 20, 2000
© 2000 Oxford University Press
Racial Variation in Prostate Cancer Incidence and in Hormonal System Markers Among Male Health Professionals
Affiliations of authors: E. A. Platz, Department of Nutrition, Harvard School of Public Health, Boston, MA; E. B. Rimm, W. C. Willett, E. Giovannucci, Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, and the Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston; P. W. Kantoff, Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School.
Correspondence to present address: Elizabeth A. Platz, Sc.D., M.P.H., Department of Epidemiology, The Johns Hopkins School of Hygiene and Public Health, 615 N. Wolfe St., Baltimore, MD 21205 (e-mail: eplatz{at}jhsph.edu).
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ABSTRACT |
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 TopNotes Abstract IntroductionParticipants and MethodsResultsDiscussionReferences |
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Background: Racial variation in prostate cancer incidence in the United States is pronounced, with African-American men having the highest rates. Whether differences in the distribution of known or suspected risk factors among racial groups explain this variation is unknown. Methods: We evaluated prospectively the relation between prostate cancer and race among 45 410 U.S. male health professionals aged 40–75 years in 1986. We used multivariable, pooled logistic regression to adjust the rate ratio (RR) for potential dietary and lifestyle risk factors. We also measured circulating levels of steroid hormones, sex hormone-binding globulin, and vitamin D metabolites and length of the androgen receptor gene CAG repeat in a sample of African-American (n = 43), Asian (n = 52), and white (n = 55) participants and assessed variation by race in these possible prostate epithelial cell growth mediators by use of analysis of variance. Statistical tests were two-sided. Results: The age-adjusted RR for prostate cancer was 1.73 (95% confidence interval [CI] = 1.23–2.45) for African-American men compared with white men. After multivariate adjustment, the RR increased to 1.81 (95% CI = 1.27–2.58). The rate of prostate cancer did not differ between Asians and whites. Steroid hormone and 1,25-dihydroxyvitamin D levels did not vary appreciably by race. However, the mean number of androgen receptor gene CAG repeats was lower among African-Americans (mean ± standard deviation = 20.1 ± 3.5) than among whites (22.1 ± 3.1; P = .007) and Asians (22.1 ± 3.9; P = .009). Conclusions: Our results confirm the elevated incidence of prostate cancer among African Americans and show that it is not explained by differences in the distribution of possible dietary and lifestyle risk factors in this cohort. Racial variation in length of the androgen receptor gene CAG repeat may explain a small part of the excess risk of prostate cancer among African-American men in this cohort.
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INTRODUCTION |
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TopNotesAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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Racial variation in prostate cancer rates in the United States is pronounced, with African-Americans having an incidence rate 1.5 times that of whites and nearly three times that of men of Asian origin (1). The prostate cancer mortality rate for African-American men is twice that of white men, and stage-specific survival in African-American men is poorer than in white men (1). Reduced access to health care may contribute to the later stage at diagnosis in African-Americans, but it is unlikely to account for the difference in stage-specific survival (1).
Similar to race, the other known risk factors of prostate cancer are primarily nonmodifiable; these include older age and a family history of prostate cancer. Possible modifiable risk factors are now beginning to emerge, including those associated with increased risk, such as intake of saturated fat (2) and calcium (3), and those are related to decreased risk, such as tomato products (4), which contain the carotenoid lycopene. The distribution of these possible risk factors may differ by racial group and may, thus, explain some of the observed variation in incidence rates by race. Heterogeneity by race in normal ranges of several possible determinants of prostate epithelial cell growth may also contribute to differences in prostate cancer rates. These include plasma levels of androgens and sex hormone-binding globulin (5–9), insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) (10–12), 1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25(OH)D] (13–16), and length of the androgen receptor (AR) gene CAG repeat (17–20).
To examine whether racial variation in prostate cancer incidence and aggressiveness is evident among men of similarly high educational status and whether variation in risk might be explained by known or suspected dietary and lifestyle risk factors for prostate cancer, we estimated the association between race and prostate cancer risk in a large cohort of U.S. male health professionals, who, during the course of 10 years of follow-up, have provided detailed dietary and lifestyle exposure data. In addition, to investigate the possible existence of racial variation in determinants of prostate epithelial cell growth, we determined the length of the AR gene CAG repeat and circulating levels of sex steroid hormones and of the vitamin D metabolites 1,25(OH)2D and 25(OH)D in a subset of cohort members without cancer.
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PARTICIPANTS AND METHODS |
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TopNotesAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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Study Population
Participants were members of the Health Professionals Follow-up Study, an ongoing prospective study of heart disease and cancer among 51 529 male dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, and podiatrists. Men who were aged 40–75 years at enrollment in 1986 completed a baseline questionnaire, which included questions on major ancestry, medical history, diet, and other lifestyle exposures. We updated exposure and disease information, including diagnosis of prostate cancer, biennially by mailed follow-up questionnaires. Deaths were reported by family members or by the postal system in response to the follow-up questionnaires or were identified through a search of the National Death Index (21). The overall follow-up response is 94%. We excluded 3749 men who were diagnosed with any cancer (except nonmelanoma skin cancer) before 1986 (4% of the cohort) or had returned an invalid dietary questionnaire in 1986 (3% of the cohort). We also excluded another 2367 (4.6% of the cohort) men who did not report their major ancestry. The analytic cohort thus included 45 410 men. The Health Professionals Follow-up Study was approved by the Human Subjects Committee of the Harvard School of Public Health, Boston, MA.
Ascertainment and Classification of Prostate Cancer Cases
After receiving written consent from the participants or their next of kin, we obtained medical and pathology records for each reported prostate cancer diagnosis. A study physician blinded to exposure information reviewed the records for confirmation of adenocarcinoma of the prostate gland and extracted from the records the stage (22) (organ confined or extraprostatic) and Gleason histologic grade (23) of the tumor. In the analysis, we classified cases as organ confined/low grade (stage A or B and Gleason grade <7) and extraprostatic/high grade (stage C or D or Gleason grade 
7) because some risk factors may act on progression of tumors or risk factors for aggressive prostate cancers may differ from nonaggressive (2). We included tumors of unknown stage and grade along with organ confined/low grade. Too few African-American (n = 4) and Asian (n = 5) men had distant metastases or died of prostate cancer to evaluate racial variation in the most advanced disease.
We excluded incidental microscopic focal tumor [Whitmore-Jewitt stage A1 (22)] cases from the analysis because these tumors are generally indolent and are most susceptible to detection bias because of differential rates of undergoing surgery for benign prostatic hyperplasia. From 1986 through January 31, 1996, a total of 1813 cases of incident non-stage-A1 prostate cancer were confirmed in 415 860 person-years of follow-up. Of these, 746 were extraprostatic/high grade and 1067 were organ confined/low grade or unknown stage/grade.
Assessment of Race
On the baseline questionnaire, men were asked to report their "major ancestry" and were given the following categories (with the option to mark more than one category): southern European, Scandinavian, other Caucasian, Afro-American, Asian/Oriental, or other (unspecified) origin. In the main analysis, the men were assigned a single major ancestry by use of the following hierarchy: African-American, Asian, other origin, or white (southern European, Scandinavian, or other Caucasian). To assess whether the assignment of a single major ancestry for men reporting two or more ancestries influenced the observed associations with prostate cancer, two additional subanalyses were run. In the first, each man was classified by all of the races he had marked. The second included only men reporting a single major ancestry.
Assessment of Covariates
Covariates examined were those observed previously to be associated with prostate cancer overall or with advanced disease in this cohort, including body mass index (BMI; weight in kilograms divided by the square of height in meters) at age 21 years (24); height (24); vigorous physical activity (25); cigarette smoking in the 10 years prior to baseline (26); diabetes mellitus (27); vasectomy (28); tomato sauce consumption (4); and energy-adjusted intake of saturated fat (2), calcium (3), and fructose (3). In 1986, we asked men to report their current height and weight and their weight at age 21 years. We calculated BMI, a measure of adiposity, for both 1986 and at age 21 years. On the 1986 questionnaire, participants also reported weekly frequency of specific physical activities over the past year. In a previous analysis of this cohort (25), only vigorous activity appeared to be inversely related to risk of prostate cancer. To generate a physical activity score for vigorous activities, which we defined as activities using 7.0 or more MET-hours [where 1 MET-hour is the metabolic equivalent of sitting at rest for 1 hour (29)], we summed activity-specific MET-hours for running, jogging, biking, swimming, and playing tennis, squash, or racquetball. In 1986, the men reported the number of cigarettes smoked per day during each decade of life, from which the number of pack-years (number of packs of cigarettes smoked per day times the number of years that number of packs was smoked) of cigarettes smoked in the 10 years prior to baseline was estimated. The men were also asked on the 1986 questionnaire if they had ever been diagnosed with diabetes mellitus or if they had had a vasectomy. Beginning in 1988 and continuing biennially, we asked the men if they had had a screening digital-rectal examination in the past 2 years. Also, in 1994 and 1996, we asked whether they had had a screening prostate-specific antigen (PSA) test ever or in the past 2 years, respectively.
A semiquantitative food-frequency questionnaire was completed at baseline that consisted of self-reported frequency of consumption, over the past year, of listed portion sizes of 131 food items; these items accounted for more than 90% of the intake of major nutrients for the participants (30). Tomato sauce intake was obtained directly from the food-frequency questionnaire. Intake of total energy, saturated fat, calcium, and fructose was estimated from the questionnaire by multiplying the frequency of consumption of each food by the portion size and the nutrient content per unit, which was obtained from U.S. Department of Agriculture (Washington, DC) sources (31) supplemented with other data and summing over all foods. Because nutrient and energy intakes tend to be correlated, we adjusted intake of saturated fat, calcium, and fructose for total energy by use of the residuals method (32).
Blood Analyses
In 1993 and 1994, more than 18 000 men in the cohort provided a blood specimen. Blood was collected in tubes containing sodium EDTA and was shipped on ice by overnight courier to our laboratory; on receipt, it was centrifuged, separated into plasma, buffy coat, and red blood cells, and stored in liquid nitrogen. After excluding men with a cancer diagnosis (except nonmelanoma skin cancer), in December 1996, we invited by mail all 63 African-Americans who provided blood in 1993 or 1994 and a random sample of 75 Asians and 75 whites to provide a second blood sample. Between January and September 1997, 43 African-Americans, 52 Asians, and 55 whites, or a total of 150 men, returned a second sample. The men were 47–78 years old when they provided blood in 1993 or 1994.
AR gene CAG repeat length was determined in the laboratory of P. W. Kantoff by polymerase chain reaction amplification of the region surrounding the repeat and sizing by automated fluorescence detection as described previously (20). Radioimmunoassays were used to determine plasma levels of testosterone (Diagnostic Products Corp., Los Angeles, CA), estradiol (Diagnostic Products Corp.), and androstanediol glucuronide (Diagnostic Systems Laboratory, Webster, TX). Dihydrotestosterone was determined by radioimmunoassay after celite column chromatography (33). Sex hormone-binding globulin was determined by radioimmunometric assay (Diagnostic Systems Laboratory). All assays of hormones were carried out in the laboratory of C. Longcope (Departments of Obstetrics and Gynecology and Medicine, University of Massachusetts Medical Center, Worcester). For the sex hormone analysis, four men had missing laboratory values; thus, only 146 were included in the analysis. Plasma 1,25(OH)2D and 25(OH)D levels were determined by radioimmunoassay as described previously (34,35) in the laboratory of B. W. Hollis (Department of Pediatrics, Medical University of South Carolina, Charleston). For the vitamin D analysis, an insufficient volume of plasma was available for the assay for five men, and one man had a missing laboratory value, thus leaving 144 men for analysis. Mean intrapair coefficients of variation for blinded quality-control samples were 0% for AR gene CAG repeat length (eight pairs); 4.3% for testosterone, 14.5% for dihydrotestosterone, 8.5% for androstanediol glucuronide, 19.5% for estradiol, and 12.9% for sex hormone-binding globulin (10 pairs); and 5.6% for 1,25(OH)2D and 6.7% for 25(OH)D (10 pairs).
Statistical Analysis
Because the racial groups differed in age at baseline in 1986, we computed age-standardized means and proportions for demographic and lifestyle factors by race categories. For each case definition and its association with categories of race or, in the case of whites, ethnicity, we calculated Mantel–Haenszel summary rate ratios (RRs) and corresponding 95% confidence intervals (CIs) (36). We used pooled logistic regression, which approximates Cox proportional hazards regression (37), to estimate multivariate RRs for each racial group or white ethnicity after adjusting for potential confounders. For the race analysis, all models included terms for African-American, Asian, and other ancestry compared with white. Because the other ancestry group is likely to be of heterogeneous composition, we do not present the findings for this group.
In the multivariate models, we adjusted for BMI at age 21 years (quintiles of kg/m2); height (quintiles of inches); vigorous physical activity (quintiles of MET-hours/week); cigarette smoking in the 10 years prior to baseline (quintiles of pack-years); diabetes mellitus (yes or no); vasectomy (yes or no); total energy intake (quintiles of kcal/day); tomato sauce consumption (four categories of servings per day); and energy-adjusted intakes of saturated fat (quintiles of g/day), calcium (quintiles of mg/day), and fructose (five categories of g/day). We also examined whether controlling for alternative expressions of recent smoking, including updated current smoking dose and updated pack-years smoked in the past 10 years, influenced the association between race and prostate cancer risk. These results were essentially the same as when we controlled for pack-years smoked in the 10 years prior to baseline, the expression we used previously (26). We did not include a term for having a father or brother with prostate cancer because family history may capture genetic predisposition that is associated with race; thus, controlling for family history could attenuate the relation between race and prostate cancer risk.
For the assessment of racial variation in the plasma parameters, we adjusted for age by regressing the plasma level on age (continuous) and recentering the residuals at the predicted plasma value for the mean age (32). 1,25(OH)2D and 25(OH)D levels were additionally adjusted by the residuals method for season of year (winter—December, January, and February; spring—March, April, and May; summer—June, July, and August; and fall—September, October, and November), in which blood was drawn by including indicator variables for each season compared with spring in the linear regression model along with age. Because blood levels measured once may not be representative of typical levels over time, for each man, we used the mean of the two time-point age-adjusted plasma values. By contrast, AR gene CAG repeat length is a stable heritable attribute. Therefore, for the assessment of racial variation in CAG repeat length, we assessed repeat length only once and we did not adjust for age. To statistically evaluate if the possible plasma and genetic determinants of prostate epithelial cell growth varied among African Americans, Asians, and whites or between any two of the groups, we used analysis of variance (38). Results were similar by use of the Kruskal–Wallis test (nonparametric). All P values were two-sided. All analyses were conducted using SAS release 6.12 (SAS Institute, Inc., Cary, NC).
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RESULTS |
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Among the 45 410 men, 481 reported their major ancestry as African-American, 817 as Asian, 42 984 as white, and 1128 as other (unspecified) ancestry. Ten percent of the African-Americans and 3.5% of the Asians reported multiple ancestries. One third of those of other ancestry also reported having a white ancestry. Age-standardized means and proportions for demographic, lifestyle, and dietary factors are presented in Table 1
. The proportion of African-American and white men with a family history of prostate cancer was similar and higher than that among Asian men. African-American and Asian men had lower intakes of saturated fat, calcium, tomato sauce, and lycopene than white men and were less likely to have had a vasectomy. African-Americans consumed more fructose and had a higher prevalence of diabetes than Asians or whites. Among men without a prostate cancer diagnosis who were still alive in 1996, the proportions of men who reported having had either a digital-rectal examination or a PSA test between 1986 and 1996 were high overall, although they were slightly lower in African-American and Asian men compared with white men. This last observation suggests that screening does not account for the higher incidence of prostate cancer among African-American men in this cohort.
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After adjustment for the differing age distribution at entry into the cohort at baseline by residuals analysis, there was no statistically significant difference (P = .8) in the mean age at prostate cancer diagnosis among African-Americans (68.6 ± standard deviation 2.2 years), Asians (69.0 ± 2.2 years), and whites (68.8 ± 2.2 years).
Compared with white men, the age-adjusted RR of prostate cancer was 1.73 (95% CI = 1.23–2.45) for African-American men (Table 2). The rate of prostate cancer was nearly identical in Asian and in white men. After adjustment for known and suspected dietary and lifestyle prostate cancer risk factors, the RR for prostate cancer among African-American men increased to 1.81 (95% CI = 1.27–2.58; P = .001). African-American men had a higher risk of both extraprostatic/high-grade and organ-confined/low-grade disease, whereas Asians did not differ from whites for either aggressive or nonaggressive tumors. Regardless of whether African-Americans and Asians who reported multiple ancestries were included in each category they checked (RR of prostate cancer = 1.84 for African-American men and RR = 0.99 for Asian men) or whether the analysis was restricted to men who reported only a single ancestry (RR of prostate cancer = 1.96 for African-American men and RR = 0.95 for Asian men), the RRs were essentially unchanged.
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rate ratios (RRs) and 95% confidence intervals (CIs) for prostate cancer according to major ancestry in the Health Professionals Follow-up Study (1986 to 1996)
Men of southern European (RR = 1.01; 95% CI = 0.90–1.14) or Scandinavian (RR = 1.08; 95% CI = 0.93–1.26) heritage did not differ in risk of prostate cancer from men of other white ancestry in multivariate analysis. In age-adjusted analysis, southern European men had a slightly reduced risk of extraprostatic/high-grade prostate cancer relative to men of other white ancestry (RR = 0.89; 95% CI = 0.74–1.06), and Scandinavian men had a slightly increased risk (RR = 1.13; 95% CI = 0.90–1.42). Because many of the recently identified possible risk factors for prostate cancer appear to be more strongly associated with aggressive than with nonaggressive disease and the distribution of some of these factors, such as intake of tomato sauce and calcium, varies by white ethnicity, we evaluated whether these factors could account for the differences in incidence of extraprostatic/high-grade disease by white ethnicity. After multivariate adjustment, the relative risks of extraprostatic/high-grade prostate cancer in southern European and Scandinavian men relative to other white men were both modestly attenuated (RR = 0.93 [95% CI = 0.77–1.11] and RR = 1.06 [95% CI = 0.84–1.33], respectively). In a comparison of Scandinavian men with southern European men, the age-adjusted RR for extraprostatic/high-grade disease was 1.27 (95% CI = 0.95–1.37), which was attenuated to 1.14 (95% CI = 0.90–1.30) after controlling for the known and suspected dietary and lifestyle risk factors. There was no difference in incidence of organ-confined/low-grade disease among the white ethnicities either before or after multivariate adjustment.
Although prostate cancer incidence was elevated among both younger and older African-American men compared with their white counterparts, the magnitude of the association was greater in younger African Americans (<69 years: RR = 2.05; 95% CI = 1.34–3.14) than in older African-Americans (69 years: RR = 1.56; 95% CI = 0.82–2.97).
In the subset of 150 of the cohort participants, African-American men had fewer AR gene CAG repeats than either white (P = .007) or Asian (P = .009) men (Table 3). Mean numbers of repeats were identical for Asians and whites (P = .9). The proportion of men with 19 or fewer repeats (shortest tertile) was 42% for African-Americans, 27% for whites, and 27% for Asians. No statistically significant differences were evident among the three racial groups in plasma levels of testosterone, dihydrotestosterone, estradiol, and sex hormone-binding globulin or in the ratios of estradiol to testosterone, androstanediol glucuronide to testosterone, dihydrotestosterone to testosterone, estradiol to sex hormone-binding globulin, and testosterone to sex hormone-binding globulin (Table 3). Plasma levels of androstanediol glucuronide did differ among the racial groups (P = .02), with white men having higher levels than African-American (P = .006) or Asian (P = .04) men. There was no variation in plasma levels of 1,25(OH)2D by racial group (P = .3) (Table 3). Levels of 25(OH)D were lowest in African-Americans, intermediate in Asians, and highest in whites (P<.001).
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DISCUSSION |
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TopNotesAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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In a cohort of middle-aged U.S. men of a similarly high educational level, the prostate cancer incidence rate was almost twice as high in the African-American men than in the white men, even after taking into account differences in distribution of most of the known and suspected dietary and lifestyle prostate cancer risk factors. The elevated prostate cancer rate in the African-American men in our study reflects the underlying excess rate seen in African-American men in the U.S. population. Although Asian men born in or immigrating to the United States are generally at lower risk of prostate cancer than white men, in this cohort, no difference in prostate cancer incidence was observed in the two groups.
The elevated prostate cancer risk among African-Americans in this cohort is unlikely to be due to differential detection of prostate cancer. Because they are all health-care professionals, the men in this cohort are likely to be of similar socioeconomic status and to have comparable access to medical care. Indeed, the proportion of men who had had either a screening digital-rectal examination or a PSA test by 1996 was similar among the racial groups examined. In addition, the relative risk of extraprostatic/high-grade tumors, which are more likely to be symptomatic at diagnosis and thus less susceptible to bias due to differential screening practices, was also elevated in African-American men as compared with white men.
The finding that the risk of both organ-confined/low-grade and extraprostatic/high-grade tumors was higher in African-American men than in white men suggests that factors influencing the onset of prostate cancer differ between the two racial groups. The relative risk of extraprostatic/high-grade tumors among African-Americans was even greater than that for organ-confined/low-grade tumors, suggesting that factors affecting the progression of prostate tumors may also differ. Previously in this cohort, vigorous physical activity (25), cigarette smoking in the 10 years prior to baseline (26), tomato sauce consumption (4), and intake of calcium (3) and fructose (3) were shown to be associated primarily or more strongly with aggressive, metastatic, or fatal prostate cancer (Table 4). In this analysis, even after accounting for any differences in the distribution of exposure to dietary and lifestyle factors among the racial groups, the marked elevation in risk of extraprostatic/high-grade disease in African-Americans as compared with whites persisted.
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The risk of prostate cancer among the Asian men in this cohort was similar to that among white men, rather than lower, as might have been expected on the basis of national and international variations in prostate cancer rates. From a review of surnames, Asian ancestry in this cohort appeared to include the Far East, the Indian subcontinent, and the Middle East. The heterogeneity in composition of this racial group is unlikely to explain the similar rate of prostate cancer between Asians and whites. Although prostate cancer rates vary among these countries, they are all substantially lower than those rates for white Americans (39). The prostate cancer risk in Asian immigrants to the United States and in second-generation Asian-Americans begins to approach that of whites (40), presumably because of changes away from traditional Asian dietary and lifestyle patterns. Of the 592 men of Asian heritage who responded to the full-length 1992 Health Professionals Follow-up Study questionnaire, on which they were asked about place of birth and place of residence at ages 15 and 25 years, 23% reported that they were born outside the United States. At age 15 years, only one of the men born outside the United States resided outside the United States, and at age 25 years, none of the men born outside the United States resided outside the United States. Thus, the men of Asian heritage in this cohort may be less likely to have a traditional Asian diet and lifestyle, which may, in part, explain why their risk of prostate cancer was similar to that of the white men in this cohort.
In our study, men of Scandinavian heritage appeared to consume more calcium than did other white men (data not shown), high intake of which is associated with an increased risk of aggressive prostate cancer in this cohort (3). Conversely, men of southern European heritage appeared to consume more tomato sauce (data not shown), high intake of which is associated with a decreased risk of aggressive prostate cancer in this cohort (4). For extraprostatic/high-grade disease, in age-adjusted analyses, southern European men did have a slightly (but not statistically significantly) reduced risk, whereas Scandinavian men had a slightly (but not statistically significantly) increased risk compared with men of other white heritage. After we controlled for the known and suspected dietary and lifestyle prostate cancer risk factors, these associations were attenuated, possibly suggesting that dietary variations, rather than genetic constitution, account for some of the modest difference in risk of aggressive disease between southern Europeans and Scandinavians.
The development and progression of prostate tumors are influenced by androgens, including testosterone and dihydrotestosterone (41). Whether normal range differences in sex hormone levels by race could account for the variation in prostate cancer risk among different races is unknown. Several relatively small studies have examined the existence of racial variation in circulating levels of sex hormones. Two studies of young adult men (42,43) found that African-Americans have 10%–20% higher plasma testosterone levels than whites. Plasma androstanediol glucuronide levels were similar in African-American and in white men but lower in Japanese men (43). Among older men, African-Americans had a higher dihydrotestosterone-to-testosterone ratio than Asians, and levels for whites were intermediate (44). In a subset of our cohort of middle-aged men, we observed no statistically significant differences in plasma sex steroid hormone levels, including testosterone and the ratio of dihydrotestosterone to testosterone, among these racial groups, with the exception of androstanediol glucuronide levels, which were highest in whites and similarly lower in Asians and African-Americans. Androstanediol glucuronide is a metabolite of dihydrotestosterone, the most potent intraprostatic androgen. Because dihydrotestosterone is produced both intraprostatically and peripherally, circulating levels may not be a good indicator of intraprostatic levels. Instead, androstanediol glucuronide has been used as a surrogate marker of dihydrotestosterone (43). Nevertheless, the differences that we observed in adult androstanediol glucuronide levels cannot account for the higher rates of prostate cancer among African-Americans in this cohort. It is still possible, however, that there are racial differences in steroid hormone levels early in life that become attenuated with age.
Both androgen levels and the AR, which mediates the effect of testosterone and dihydrotestosterone in androgen-responsive tissues, determine androgenicity (45). The first exon of the AR gene includes a polymorphic CAG repeat. Epidemiologic studies (17–20) have reported RRs of 1.2–2.1 for prostate cancer when comparing shorter to longer lengths. African-Americans have been reported to have shorter AR gene CAG repeats than whites, and Asians have the longest repeats. One study (46) showed mean repeat lengths of 20.1 for African Americans, 21.9 for whites, and 22.4 for Asians; another study (17) found mean repeat lengths of 18.5 for African-Americans, 21.0 for whites, and 21.9 for Asians; a third sudy (47) found mean repeat lengths of 19.0 for African-Americans and 21.0 for whites. In the present study, we also observed shorter mean AR gene CAG repeats in a subset of the African-American participants in the Health Professionals Follow-up Study cohort. Unlike the two studies that have evaluated repeat length differences between whites and Asians, we did not observe a difference between whites and Asians in the cohort subset (both means = 22.1). Nevertheless, the pattern of shorter repeats among African-Americans compared with whites and Asians and no difference in mean repeats among whites and Asian, is consistent with the pattern of variation in prostate cancer risk observed among the Health Professionals Follow-up Study cohort.
Given that the mean length of the AR gene CAG repeat differs between African-American and white men and that shorter AR gene CAG repeats are associated with an increased risk of prostate cancer, we assessed the extent to which the racial difference in repeat length might explain the difference in prostate cancer risk between African-Americans and whites. If the proportions of African-Americans and whites with fewer than 20 CAG repeats are approximately 50% and 30%, respectively, and if the RR for prostate cancer for fewer than 20 repeats compared with greater than or equal to 20 is about 2.0, then the observed RR for prostate cancer solely due to differences in CAG repeats comparing African-Americans to whites would be 1.15. Thus, the length of the AR gene CAG repeat is unlikely to be the sole explanation for the difference in the risk of prostate cancer observed among African Americans and whites in this study and in the U.S. population.
Vitamin D metabolites may also influence the risk of prostate cancer incidence and progression. In vitro evidence suggests that 1,25(OH)2D, the biologically active form of vitamin D, can inhibit growth of prostatic epithelial cells (48–52). Intake of cholecalciferol (vitamin D), a precursor of 1,25(OH)2D, is not clearly associated with prostate cancer risk (3). However, calcium intake, which lowers production of 1,25(OH)2D, is directly associated with prostate cancer risk (3). 1,25(OH)2D is produced in the kidney by 1-
-hydroxylation of its precursor, 25(OH)D, which is produced in the liver by 25-hydroxylation of vitamin D; circulating levels of 1,25(OH)2D are under tight homeostatic regulation. Four nested case–control studies have evaluated circulating vitamin D levels and prostate cancer risk. One study (13) observed a strongly decreasing risk of prostate cancer with higher 1,25(OH)2D levels, in particular along with lower 25(OH)D levels. Two studies (15,16) found a nonstatistically significantly reduced risk of prostate cancer among men with high levels of both 1,25(OH)2D and 25(OH)D, although there were no consistent patterns for the two vitamin D metabolites individually. The fourth study (14) did not observe associations for either metabolite. We observed no racial variation in circulating 1,25(OH)2D levels in our study; therefore, an endocrine role of 1,25(OH)2D is unlikely to explain racial variation in prostate cancer incidence. Although we did not examine the vitamin D receptor, differences among racial groups have been observed in the prevalence of polymorphisms in the receptor (53).
We did, however, observe racial variation in 25(OH)D. As in the study by Corder et al. (13), African-American men had lower levels. Because circulating 25(OH)D levels are determined, in part, by sun exposure, our observation is consistent with the hypothesis that individuals with more skin pigmentation tend to have lower 25(OH)D levels. Both normal and malignant prostate cell lines express 1--hydroxylase and can convert 25(OH)D to 1,25(OH)2D in vitro (54). Treatment of primary cultures of normal and malignant prostate epithelial cells with 25(OH)D results in growth inhibition (55,56). Whether the lower circulating levels of 25(OH)D in African-American men result in low intraprostatic production of 1,25(OH)2D and, thus, possibly may be responsible for the elevated risk of prostate cancer in African-American men remains to be investigated.
The IGF axis may also influence prostate cancer risk. Studies (10–12) have suggested that higher plasma levels of IGF-I are associated with an increased risk of prostate cancer. We reported previously (57) that white men had the highest median IGF-I levels compared with Asians and African-Americans, whose levels were similar. Median plasma concentrations of IGFBP-3, which modulates the bioavailability of IGF-I (58) and may induce apoptosis independently of its effects on IGF-I (59), were similar in white and Asian men but were more than 13% lower in African-American men (57), a finding similar to that of Tricoli et al. (60). The lower IGF-I blood levels relative to IGFBP-3 levels among Asian men are consistent with their lower prostate cancer incidence internationally but not in this cohort. Although differences in circulating IGF-I do not appear to account for the greater prostate cancer risk among African-American men in the United States or in this cohort, their lower levels of IGFBP-3 may be contributory.
Several aspects of the current study warrant discussion. The Health Professionals Follow-up Study is large and has a long duration of follow-up, although the numbers of African-American (n = 481) and Asian (n = 817) members are small relative to the number of white members (n = 42 984). The racial composition of this cohort was dependent on the pool of middle-aged health professionals at the time that the cohort was assembled in 1986. Nevertheless, we were able to detect a statistically significant difference (P = .001) in risk of prostate cancer in the African-American participants as compared with the whites. The excess rate of prostate cancer among African-Americans is well documented by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program1 (61). Because race encompasses multiple components, including genetics, diet, lifestyle, and access to medical care, the strength of our analysis was that we were able to adjust for known and suspected prostate cancer risk factors for which the distribution of exposure may vary by racial group.
We had expected that the modifiable and other known or suspected prostate cancer risk or protective factors would explain some portion of the higher prostate cancer risk in the African-American men in this cohort as compared with the white men. However, when we simultaneously adjusted for multiple possible prostate cancer risk or protective factors observed previously in this cohort, the RR was not attenuated. We cannot exclude the possibility that measurement error in the assessment of the factors, the extent of which may be similar (i.e., nondifferential measurement error) or different (i.e., differential measurement error) for each racial group, resulted in the factors failing to explain some of the racial variation in incidence. Although nondifferential measurement error remains a possibility, we do not believe that it is present to an extreme extent because we have observed associations between these factors and either prostate cancer overall or advanced disease in previous analyses (2–4,24–28). We did not perform measurement error correction because we have not conducted validation studies of these factors separately by racial group. We also cannot exclude the possibility of differential misclassification of the factors that may have resulted from modeling categorized covariates that were originally continuous and measured with nondifferential error (62).
Whether the African-American, Asian, and white participants in this study and, in particular, the subset of men included in the plasma hormone and AR gene CAG repeat and racial variation analyses are representative of other men residing in the United States who would classify themselves similarly is unknown. However, as in other studies, the African-American men in our study also had a mean AR gene CAG repeat length that was two repeats shorter than that in whites, suggesting comparability between the African-American participants in our study and those in other studies. We did not adjust for differences in the distribution of anthropometric factors, such as BMI and height, by race in the analysis of heterogeneity in the plasma parameters because the magnitude of these factors may be a manifestation of hormone levels. A limitation of having measured these factors in plasma and having determined them only twice within a few years in older adulthood is that these levels may not be well correlated with levels at etiologically relevant moments or with intraprostatic concentrations.
In summary, African-American men in this large, highly educated cohort were at nearly twice the risk of prostate cancer compared with white men, even after adjustment for a number of known and suspected prostate cancer risk factors. In a subset of these men, African-Americans had fewer AR gene CAG repeats on average, although the difference in the prevalence of short CAG repeats is unlikely to account for the large difference in risk of prostate cancer by race. Whether the lower circulating level of 25(OH)D in African-American men influences their higher prostate cancer incidence requires additional study. Urgently needed is continued identification of modifiable exposures and inherent factors that may be beneficially influenced by modifiable factors that vary among racial groups in the United States and that may explain the markedly higher rate in African-American men.
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NOTES |
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1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
Supported by Public Health Service grants CA55075 and CA72036 (National Cancer Institute) and HL35464 (National Heart Lung and Blood Institute), National Institutes of Health, Department of Health and Human Services; and by the Commonwealth of Massachusetts Prostate Cancer Awareness Program.
We thank Richard Chambers, Linlin Chen, Mira Kaufman, Kate Markham, Alan Paciorek, Jill Arnold, Kerry Demers, Elizabeth Frost-Hawes, Alvin Wing, and Mildred Wolff for their continued help in conducting the Health Professionals' Follow-up Study. We also thank Dr. Bruce W. Hollis (vitamin D assays), Dr. Christopher Longcope and members of his laboratory, Charlene Franz, Charlotte Bukowski, and Mary Ann Grigg (steroid hormone assays), and Carsta Cieluch in Dr. Philip W. Kantoff's laboratory (androgen receptor gene CAG repeat assay) for their laboratory expertise.
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Manuscript received April 19, 2000; revised September 1, 2000; accepted October 16, 2000.
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M. Zitzmann, M. Depenbusch, J. Gromoll, and E. Nieschlag Prostate Volume and Growth in Testosterone-Substituted Hypogonadal Men Are Dependent on the CAG Repeat Polymorphism of the Androgen Receptor Gene: A Longitudinal Pharmacogenetic Study J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2049 - 2054. [Abstract] [Full Text] [PDF]
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B. N. Ames The Metabolic Tune-Up: Metabolic Harmony and Disease Prevention J. Nutr., May 1, 2003; 133(5): 1544S - 1548. [Abstract] [Full Text] [PDF]
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C. Ntais, A. Polycarpou, and J. P. A. Ioannidis Association of the CYP17 Gene Polymorphism with the Risk of Prostate Cancer: A Meta-Analysis Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 120 - 126. [Abstract] [Full Text] [PDF]
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S. M. Gapstur, P. H. Gann, P. Kopp, L. Colangelo, C. Longcope, and K. Liu Serum Androgen Concentrations in Young Men: A Longitudinal Analysis of Associations with Age, Obesity, and Race. : The CARDIA Male Hormone Study Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1041 - 1047. [Abstract] [Full Text] [PDF]
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C. L. Bennett, D. K. Price, S. Kim, D. Liu, B. D. Jovanovic, D. Nathan, M. E. Johnson, J. S. Montgomery, K. Cude, J. C. Brockbank, et al. Racial Variation in CAG Repeat Lengths Within the Androgen Receptor Gene Among Prostate Cancer Patients of Lower Socioeconomic Status J. Clin. Oncol., September 1, 2002; 20(17): 3599 - 3604. [Abstract] [Full Text] [PDF]
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M. Zitzmann, M. Brune, B. Kornmann, J. Gromoll, S. von Eckardstein, A. von Eckardstein, and E. Nieschlag The CAG Repeat Polymorphism in the AR Gene Affects High Density Lipoprotein Cholesterol and Arterial Vasoreactivity J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4867 - 4873. [Abstract] [Full Text] [PDF]
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