Abstract
ObjectiveTo investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can).MethodsMe-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation.ResultsIn men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph−/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph−/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83).ConclusionTSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.
Highlights
In men, compared with the 1st quintile, total serum cholesterol (TSC) concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%confidence intervals (CI): 0.88, 1.00)
Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph2/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87)
Hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph2/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83)
Summary
Since the 1980s several epidemiological studies have reported an association between higher total serum cholesterol (TSC) levels and lower overall or site-specific cancer incidence and mortality [1,2,3,4,5,6,7,8,9], whereas others found higher cancer risk in people with high TSC levels [10,11,12,13], no significant relation [14,15,16,17,18], or a U-shaped association, that is both low and high TSC levels being significantly associated with increased cancer risk [19].It has been suggested that the observed inverse associations have to be attributed to an effect of preclinical cancer or disease on cholesterol levels (i.e. metabolic depression or increased utilization of cholesterol during carcinogenesis [20]) rather than reflecting a true causal relationship. The hypothesis of reverse causation is strongly supported by a recent Mendelian randomization study [21] and by the observation that the inverse associations between high cholesterol levels and cancer risk and mortality weakened or even disappeared when the first few years of study follow-up were excluded [1,9,22]. Some studies found inverse associations with time lags of 4 or even more years between baseline cholesterol level and cancer diagnosis [7,20,23], so the possibility that there may be a direct effect of low cholesterol on cancer can still not be completely ruled out. More recent studies [24,25] on cholesterol and cancer incidence, including partly data used in this study [25], added additional evidence for the reverse causation hypothesis again. Relatively modest sample sizes and differences in study populations, length of follow-up, study endpoints and statistical procedures may all have contributed to the lack of consistency in results of previous studies
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