Average total and HDL cholesterol values for the study population at baseline were 241.2 mg/dl (standard deviation (SD) = 45.1) and 46.3 mg/dl (SD = 12.3), respectively. Pearson correlations between the baseline and 3 year measurements for total and HDL cholesterol were high (r=0.74 and r=0.77, respectively). Total cholesterol and HDL cholesterol were unrelated (r=0.01).
Men with higher serum total cholesterol concentration tended to have lower education, and reported greater consumption of saturated fat, whereas those with higher HDL cholesterol levels were leaner, physically more active, and consumed more alcohol, compared with men in the lowest cholesterol quintiles (). Age, cigarettes per day, and years of smoking did not differ substantially by total or HDL cholesterol quintile.
Baseline characteristics of participants, according to serum total cholesterol and HDL cholesterol, ATBC Cancer Prevention Study Cohort, 1985–2003 (N=29,093)a
During 18.0 years of follow-up (median 14.9 years), 7,545 incident cancer cases were identified. Higher serum total cholesterol was associated with decreased overall cancer incidence in the multivariate model (i.e., comparing highest to lowest quintiles, RR=0.85, 95% CI=0.79–0.91; p trend <0.0001; ). The nonparametric regression plot showed a pattern similar to the categorical analyses, with the multivariate RR decreasing linearly with increasing total cholesterol (). To minimize the impact of pre-clinical malignancy on serum cholesterol concentrations in our study, we conducted a lag analysis that excluded cases diagnosed within the first nine years of follow-up which showed the inverse association substantially attenuated and no longer statistically significant (RR=0.96, 95% CI=0.87–1.06). Progressive attenuation was observed with the exclusion of the first three, nine, twelve and fifteen years of follow-up ().
Relative risks (RR) and 95% confidence intervals (CI) of cancer in relation to serum total cholesterol, 1985–2003 (N=29,093)
Nonparametric Regression Curve for the Association between Total Cholesterol and HDL Cholesterol and Cancer Risk
The inverse relation of serum total cholesterol was particularly evident and significant for cancers of the lung and liver (highest versus lowest quintile, RR=0.81 (95% CI=0.72–0.92; p for trend=0.0006) and 0.66 (95% CI=0.43–1.01; p for trend=0.007), respectively) ( and ). As in the analysis of all cancers combined, however, these associations were no longer significant when we excluded cases ascertained during the first nine years of follow-up (lung cancer RR (95% CI) = 0.93 (0.78–1.11), 1,327 cases; liver cancer RR (95% CI) = 0.89 (0.47–1.67), 92 cases). Higher serum cholesterol was also associated with decreased risks of the prostate, colorectal, and kidney cancers (albeit with marginal statistical significance), and were also attenuated in the nine year lag analysis (highest versus lowest quintile, RR = 0.95, 1.18, and 1.04, for the three sites respectively). Total cholesterol concentrations were unrelated to risk of the other cancer sites examined, and the findings remained essentially unchanged when we used total cholesterol measured in the third year of follow-up or used an average of the two cholesterol determinations (data not shown).
HRs and 95% CI for the 5th versus 1st quintile of Total Cholesterol (figure 2-a) and HDL Cholesterol (figure 2-b) and Cancer Risk
We examined whether the serum total cholesterol–cancer associations were modified by other factors and found that the associations were largely similar across various subgroups of men defined by age (<60 and 60+ years), BMI (<25, 25–29.9, and 30+ kg/m2), total fat and alcohol intake (tertiles), years of smoking (tertiles), cigarettes smoked daily (tertiles), and the α-tocopherol and β-carotene trial supplementation groups (all p for interaction ≥ 0.1; data not shown).
Higher serum HDL cholesterol was modestly, but significantly, associated with decreased cancer incidence overall in multivariate models (; comparing highest to lowest quintile, RR=0.89, 95% CI=0.83–0.97; p trend=0.01). The nonparametric regression curve () showed a pattern similar to that of the categorical analyses, with the multivariate RR decreasing with increasing serum HDL cholesterol up to approximately 55 mg/dl. The inverse association remained significant after exclusion of cases diagnosed during the first 12 years of follow-up (RR (95% CI)=0.85 (0.75–0.98), p trend=0.01; n=2,365 cases), and was similar but not statistically significantly after excluding the first 15 years of observation (RR (95% CI)=0.85 (0.69–1.02) p trend=0.10; n=1,002 cases).
Relative risks (RR) and 95% confidence intervals (CI) of cancer in relation to serum HDL cholesterol, 1985–2003 (N=29,093)
The weak inverse relation of HDL cholesterol was largely attributed to cancers of the lung, prostate, liver, and hematopoietic system: RR (95% CI) for highest versus lowest quintiles for these sites, respectively, were 0.89 (0.78–1.01), p trend =0.19; 0.89 (0.75–1.06), p trend =0.12); 0.61 (0.38–0.97), p trend=0.05); and, 0.71 (95% CI=0.49–1.04, p trend=0.03). When we excluded cases diagnosed in the first 9 years of follow-up, however, only the inverse associations with lung and liver cancer remained suggestive (RR (95%CI) = 0.84 (0.69–1.01) and 0.74 (0.39–1.44), respectively). Exclusion of cases ascertained during the first 12 years of follow-up also did not eliminate these associations, although the number of cases were small (RR for lung cancer=0.86 (0.68–1.09) and RR for liver cancer=0.49 [0.20–1.23]). In contrast, the inverse associations with prostate and hematopoietic cancers was not apparent after excluding cases from the first nine years (RR’s (95% CI) of 0.94 (0.75–1.16) and 1.76 (0.65–2.14), respectively). Results remained essentially unchanged when we used HDL cholesterol measured in the third year of follow-up or used the average of the two HDL cholesterol values (data not shown).
In exploratory analyses, associations between HDL cholesterol and cancer were largely similar across other subgroups of men defined by age (<60 and 60+ years), BMI (<25, 25–29.9, and 30+ kg/m2), total fat and alcohol intake (tertiles), years of smoking (tertiles), cigarettes smoked daily (tertiles), and the α-tocopherol and β-carotene trial supplementation groups (all p for interaction ≥ 0.05; data not shown).