In this large prospective study, high use of garlic and ever use of grape seeds was associated with a lower risk of hematologic malignancies. In contrast, we found no association between risk of total hematologic malignancies and use of any of the individual vitamins, minerals, or other specialty supplements assessed.
Over-the-counter multivitamins are the most widely used dietary supplements in the United States (19
). Although experimental studies suggested favorable effects of individual vitamins on various biological processes involved in tumorigenesis (20
), a systematic review and a recent analysis from the Women’s Health Initiative cohorts found no evidence that multivitamin supplements could prevent common cancers, but hematological malignancies have not been examined in these reports (24
). The few previous studies on dietary supplement use and risk of hematologic malignancies have been mostly focused on NHL and on only the most commonly used supplements (9
). Together, results for multivitamin use across studies, including ours, are inconsistent for multivitamin use, but generally show no associations of use of supplemental vitamin A (primarily retinol), vitamin C, or vitamin E with hematologic malignancies.
A number of experimental studies have suggested that garlic or specific garlic compounds, most prominently organic sulfur compounds (such as allicin, S-allylmercaptocysteine, S-allylcysteine, diallyl sulfide, diallyl disulfide, and diallyl trisulfide), could prevent cancer through mechanisms that may include the modulation of carcinogen metabolism, inhibition of DNA adduct formation, upregulation of antioxidant defenses and DNA repair systems, and the promotion of mitotic arrest and apoptotic cell death of cancer cells (26
). In contrast to these in vitro
and in vivo
experimental investigations, epidemiological studies have yielded mixed results (34
). Specifically, some case-control studies have suggested reduced risk of cancers of the stomach, larynx, breast, and prostate with the use of allium vegetables, including garlic (35
). In contrast, a prospective study found a higher risk of lung cancer for subjects who exclusively used garlic supplements (HR=1.78 [1.08–2.92]) (40
) and no association with breast (41
) or colorectal (42
) cancer. Our study is the first to investigate garlic supplements in relation to hematologic malignances and suggests a protective association in both men and women of similar magnitude.
Grape seeds are a rich source of proanthocyanidins, which possess potent anti-oxidant properties and, like many phytochemicals, have shown promising chemopreventive effects in vitro
and in animal models (43
). While the exact mechanism underlying chemopreventive effects of grape seed proanthocyanidins remains unclear, several molecular targets have been identified, including NF-κB, mitogen-activated protein kinases, and PI3K/AKT (45
). A recent randomized controlled trial in subjects with type 2 diabetes found that grape seed extracts, but not placebo, significantly improved markers of inflammation (C-reactive protein, reduced glutathione), suggesting that grape seeds have clinically relevant anti-inflammatory properties (46
). While, to our knowledge, no study has so far assessed the association of grape seed supplements with incident hematologic malignancies, a recent report from the Iowa Women’s Health Study showed that dietary proanthocyanidins were associated with a significantly reduced risk of NHL (RR=0.70 [0.52–0.94]) (9
), i.e. an effect of similar magnitude as that observed in our study. Two recent studies have similarly found associations between use of grape seed supplements and reduced risk of cancer. Specifically, we previously reported strong inverse associations between use of grape seed supplements and the risk of prostate cancer (HR 0.59 [0.40–0.86]) in the VITAL cohort (47
). In addition, use of grape seeds was associated with reduced risks of cutaneous squamous cell skin cancer (odds ratio=0.26 [0.08–0.89]) in a recent case-control study (48
), lending further support to the hypothesis that grape seed supplements may have chemopreventive properties in humans.
Strengths of this study include its prospective design, the large cohort size, and case ascertainment through the SEER cancer registry. In addition, supplement users were targeted for recruitment, and detailed information was collected on current and long-term supplement exposure (15
). Because multivitamins contain multiple nutrients, we also attempted to separate associations with specific supplemental nutrients from those due to multivitamin use only by restricting the highest category of users to participants with a 10-year average dose that was greater than what could be obtained from 10 years of daily use of a common multivitamin formulation. Thus, our results for the highest exposure category reflect high use of the individual nutrient supplement or use of a multivitamin with a high dose of the nutrient. Only 5% of the cohort moved out of the SEER catchment area over the 7 years of follow-up, and bias due to differential loss to follow-up is therefore unlikely to explain our findings. Furthermore, the availability of baseline information on personal lifestyle and medical history allowed adjustment for major potential confounding factors, including adjustment for confounding by suspected indication for supplement use, although residual confounding cannot be excluded.
On the other hand, limitations in our measurement of supplements need to be recognized. First, our 10-year dose variable for each nutrient combines information on years, frequency, and dose per day of use of each of multivitamin and individual supplements into a summary dose variable. In so doing, the individual associations with dose per day, years of use, or some other combination of these would have been missed. Second, we only ascertained the daily dose for vitamins and minerals but not specialty supplements, in part because there is evidence that the advertised dose of specialty supplements can vary substantially from the actual dose (49
). Third, supplement use was ascertained through participant self-report. However, a previous study demonstrated high reproducibility and validity for the self-reported information on supplement use in the VITAL cohort (50
). Fourth, our result for grape seed was based on a crude variable of ever/never use over the 10 years before baseline. However among users, 84% took the supplements at least 4 days per week, 46% had taken it for at least 3 years before baseline, and 62% were still taking the supplement at baseline and would, therefore, have accumulated additional use after baseline. Measurement errors from these sources are likely to be non-differential and would therefore attenuate our risk estimates, possibly masking small associations.
In addition, our study may be limited by the fact that some hematologic malignancies may require a prolonged period of time to develop and become clinically manifest. Although we were able to follow our study cohort for an average of 6.5 years, we cannot exclude the possibility that this follow-up is insufficient to observe a true association between supplement intake and some incident hematologic malignancies. Furthermore, stratified analyses of the associations between use of supplements and risk of hematologic malignancies were limited in power, in part due to the diversity of hematologic malignancies and low incidence of these cancers; as a result, we were unable to conduct statistically meaningful subgroup analyses exploring whether the associations of 10-year average use of garlic, grape seed, and multivitamin supplements differed by specific tumor morphology. Finally, since we investigated 24 types of supplements, the possibility of chance finding due to multiple testing needs to be acknowledged.
Of some concern is the possibility of reverse causation, i.e. disease symptoms could lead to exposures (e.g. supplement use) rather than the reverse. However, for most supplements, the highest use category required many years of use, and we accounted for self-reported health in multivariable-adjusted models. Nonetheless, we additionally excluded cases arising in the first 2 years of follow-up in additional analyses. In these analyses, the HRs for high use of garlic, ever use of grape seeds, and high use of multivitamin pills were very similar to those obtained when all cases were included.
In conclusion, we observed that use of garlic and grape seeds supplements is associated with lower incidence of hematologic malignancies. Our findings suggest a possible role of these supplements in the chemoprevention of hematologic malignancies, but further, controlled studies will need to confirm these findings. The other supplements assessed in our study are unlikely to be useful for the prevention of hematologic malignancies.