In this cross-sectional sample of 2895 middle-aged and older women free of CVD and cancer, we confirmed findings from other studies that smokers and obese individuals had lower plasma concentrations of carotenoids. We also found that plasma α-carotene, β-carotene, and lycopene were positively associated with LDL cholesterol, plasma lycopene was positively associated with HbA1c and inversely associated with HDL cholesterol, and plasma β-carotene was inversely associated with CRP. These associations were independent of various lifestyle factors, clinical factors, and dietary intake of respective carotenoids.
Lower plasma concentrations of carotenoids among smokers (10
) and obese individuals (16
) have been previously reported in a number of studies. These associations may reflect both different intakes across subgroups of study subjects and metabolic effect of lifestyle and anthropometry factors on plasma carotenoids. Smoking is known to increase the production of oxygen-derived free radicals. Carotenoids, as potent antioxidants, retard the proliferation of free radicals and protect against free radical-mediated tissue damage.(26
) The interaction with free radicals results in the fragmentation and loss of carotenoid molecules.(28
) Excessive oxidative stress and depletion of antioxidants are also present among obese individuals. An alternative explanation of the inverse association between plasma carotenoids and BMI is that compared to normal weight persons, overweight or obese individuals with greater body fat storage may have lower circulating carotenoids in plasma due to a high proportion of carotenoids, as lipid-soluble compounds, being stored in adipose tissue.(10
The positive association between plasma carotenoids and serum cholesterol levels observed in previous studies (10
) reflect the fact that the lipophilic carotenoids are absorbed with dietary fats(29
) and transported in lipoproteins.(30
) In our study, though plasma carotenoids were unassociated with total cholesterol, α-carotene, β-carotene and lycopene were strongly and positively associated with LDL cholesterol, and all carotenoids except for lycopene were positively associated with HDL cholesterol after adjusting for total cholesterol. The positive association of plasma carotenoids with LDL cholesterol remained significant after multivariate adjustment. Although hypercholesterolemia is complicated with greater free radical production,(31
) it appeared that the potentially increased utilization of carotenoids in hypercholesterolemia is less biologically important in determining plasma carotenoids compared to the role of cholesterol as a non-specific carrier.
An inverse association between plasma carotenoids and blood glucose has been reported in previous cross-sectional studies,(32
) suggesting a relation between impaired glucose metabolism, increased free radical activities, and reduced antioxidant concentrations. Fewer data are available regarding the association with elevated HbA1c, an indicator of chronic hyperglycemia. Our study found that higher levels of HbA1c were associated with lower plasma concentrations of α-carotene, β-carotene and β-cryptoxanthin, which is consistent with an earlier report,(35
) but the inverse association in our study was attenuated and no longer significant after multivariate adjustment. Our finding of a positive association of plasma lycopene with HbA1c contrasted with some earlier studies.(35
An inverse association between plasma carotenoids and inflammatory markers was reported previously among elderly nuns(37
) and lung cancer patients.(38
) In adults with acute inflammatory conditions such as tuberculosis(39
) and pancreatitis,(40
) there were transient decrease in serum carotenoids and increase in CRP level, which normalize with resolution of the illness. In the Third National Health and Nutrition Examination Survey (NHANES III), serum β-carotene was strongly and inversely associated with CRP levels and white blood cell count after adjusting for carotene intake and other possible confounders.(41
) Our study results agree with this earlier study in a representative population sample by showing that high CRP was associated with low plasma α- and β-carotene after multivariate adjustment. In many inflammatory disorders, the inflammatory responses induce the release of chemical mediators and activate peripheral blood mononuclear cells, which in turn produce excessive reactive oxygen species or oxygen free radicals,(42
) and then increase the utilization of carotenoids.
In the current study, the observed associations with CVD risk factor and related biomarkers were not uniform for all carotenoids. The carotenoids differ in tissue localization and in antioxidant properties.(46
) Lutein/zeaxanthin and β-cryptoxanthin were less-reactive antioxidant compared to other carotenoids in vitro and were not associated with any CVD related biomarkers in our study. Lycopene has the most powerful antioxidant properties among major carotenoids detected in human tissues.(47
) However, our study, in consistency with others,(10
) noted that many associations observed for plasma lycopene were in directions opposite to other carotenoids, for reasons yet to be fully understood. Dietary lycopene is derived predominantly from consumption of tomatoes and tomato products.(48
) It is possible that subjects who consume large amount of lycopene-rich foods have some distinctive but un-recognized characteristics. Another possible explanation could be the different features of cis
lycopene, which were not determined in the present study.
Several potential limitations of our study deserve consideration. First, we cannot establish any cause-effect association from this cross-sectional study. Second, although we do not anticipate major effects on the blood measurement due to processing and storage, single measurement of plasma carotenoids and CVD related biomarkers could introduce non-differential misclassification, which will bias the association towards the null. This may also explain the relatively low correlation between dietary carotenoids and plasma carotenoids in the current study compared to other studies.(10
) In addition to variability in blood measurements, the diversity of carotenoid food sources also serves to reduce individual magnitudes of dietary-plasma carotenoids correlations. Of note, the Harvard Food Consumption database used USDA Agriculture Handbook no. 8 published in 1993 and had not included the most updated carotenoids values of foods. Third, although multiple factors were comprehensively adjusted for in our analyses, residual confounding from unknown or poorly measured determinants of plasma carotenoids cannot be completely ruled out. Finally, our study results apply to middle-aged and older, predominantly White women who were initially free of CVD and cancer. Studies in other populations are needed to confirm our findings.
In conclusion, we found in a cross-sectional sample of middle-aged and older women, that plasma carotenoids were associated with smoking, obesity, LDL cholesterol, HDL-cholesterol, HbA1c, and CRP levels. These associations were different among individual carotenoids, and may partially explain the observed inverse association of plasma carotenoids with CVD outcomes in previous population studies. These findings emphasize the importance of adequately controlling for confounders of plasma carotenoids in epidemiological studies of CVD.