Folate Intake, Serum Folate Levels, and Prostate Cancer Risk
Folate Intake, Serum Folate Levels, and Prostate Cancer Risk
The results of the study selection process are shown in Figure 1. We identified 367 articles in our initial electronic search; 23 remained after exclusion of duplicates and irrelevant studies. After a detailed evaluation, 10 prospective studies were selected for the final meta-analysis. A manual search of the reference lists of these studies did not yield any new eligible studies. The general characteristics of the included studies are presented in Table 1.
(Enlarge Image)
Figure 1.
Flow diagram of the literature search and studies selection process.
Five prospective cohort studies involving a total of 192,702 individuals, between 14,620 and 65,836 men were included in each study, and follow-up periods ranged from 9.0 to 17.3 years evaluated the association between dietary folate intake and the risk of prostate cancer, and the remaining 5 nested case control studies investigated the association between serum folate levels and the risk of prostate cancer for a total of 9810 individuals, between 321 and 6000 blood samples were included in each study, and follow-up periods ranged from 4.9 to 15.7 years. Furthermore, serum folate level was measured on a non-fasting sample obtained at entry to the study in all included studies. One study was conducted in the United States, 2 were performed in Australia, and the remaining 7 studies [7,8,11–13.15,16] were conducted in Europe. Study quality was assessed using the NOS system. In this study, we considered a study with a score of 8 or 9 as being of high quality. Overall, three studies had a score of 9, four studies had a score of 8, two studies had a score of 7, and one study had a score of 6.
After pooling the included studies, the summary RR illustrated that a high dietary folate intake was not associated with prostate cancer risk (RR = 1.02; 95% CI = 0.95–1.09; P = 0.598, Figure 2A), and no evidence of heterogeneity was observed (I = 0.0%; P = 0.959). The findings of the dose–response meta-analysis also suggested no association between the risk of prostate cancer and a 100 μg/day increment of dietary folate intake (RR = 1.01; 95% CI = 0.99–1.02; P = 0.433, [I = 0.0%; P = 0.784], Figure 2B). As a result, a sensitivity analysis was conducted, and after each study was sequentially excluded from the pooled analysis, the conclusion was not affected by exclusion of any specific study.
(Enlarge Image)
Figure 2.
Relative risk estimates of prostate cancer for high versus low dietary folate intake (A) and per 100 ug/day increment in folate intake for prostate cancer (B).
All studies were included in the dose–response curve between dietary folate intake and the incidence of prostate cancer. As shown in Figure 3A and illustrated by the P value for nonlinearity (P = 0.012), we found evidence of nonlinear relationships between dietary folate intake and the risk of prostate cancer. Dietary folate intake of more than 300 μg per day appeared to be associated with a non-significant reduction in the risk of prostate cancer.
(Enlarge Image)
Figure 3.
Dose-response relations for dietary folate intake (A) and serum folate levels (B).
A total of 5 prospective nest case control studies reported an association between serum folate levels and the risk of prostate cancer. The pooled analysis results for prostate cancer incidence indicated that the comparison of the high versus low categories of serum folate levels was associated with a harmful effect (RR = 1.21; 95% CI = 1.05–1.39; P = 0.008, with no evidence of heterogeneity [I = 0.0%; P = 0.724]; Figure 4A). The dose–response meta-analysis suggested that a 5 nmol/L increment of serum folate levels was associated with increased risk of prostate cancer (RR = 1.04; 95% CI = 1.00–1.07; P = 0.042, with no evidence of heterogeneity [I = 0.0%; P = 0.418], Figure 4B). Furthermore, as shown by the P value of nonlinearity (P = 0.111), there was no evidence of a potential non-linear relationship (Figure 3B).
(Enlarge Image)
Figure 4.
Relative risk estimates of prostate cancer for high versus low serum folate levels (A) and per 5 nmol/L increment in serum folate levels for prostate cancer (B).
Heterogeneity testing for the analysis identified a P value >0.10 for prostate cancer incidence. We concluded that heterogeneity is not significant in the overall analysis, suggesting that most variation was attributable to chance alone. Subgroup analyses were conducted to evaluate the effect of folate on prostate cancer risk in a specific population. Overall, we noted that a 5 nmol/L increment of serum folate levels was associated with the increased risk of prostate cancer if the duration of the follow-up less than 15 years. No other significant differences in effects were detected between dietary folate intake or serum folate levels and the risk of prostate cancer (Table 2).
A review of funnel plots could not eliminate the potential for publication bias for prostate cancer (Figure 5). The Egger and Begg test results disclosed no evidence of publication bias for prostate cancer (Egger: P = 0.694 for dietary folate intake and P = 0.181 for serum folate levels; Begg: P = 0.806 for dietary folate intake and P = 1.000 for serum folate levels; Figure 5).
(Enlarge Image)
Figure 5.
Funnel plot for per 100 ug/day increment in dietary folate intake (A) and per 5 nmol/L increment in serum folate levels for prostate cancer (B).
Results
The results of the study selection process are shown in Figure 1. We identified 367 articles in our initial electronic search; 23 remained after exclusion of duplicates and irrelevant studies. After a detailed evaluation, 10 prospective studies were selected for the final meta-analysis. A manual search of the reference lists of these studies did not yield any new eligible studies. The general characteristics of the included studies are presented in Table 1.
(Enlarge Image)
Figure 1.
Flow diagram of the literature search and studies selection process.
Five prospective cohort studies involving a total of 192,702 individuals, between 14,620 and 65,836 men were included in each study, and follow-up periods ranged from 9.0 to 17.3 years evaluated the association between dietary folate intake and the risk of prostate cancer, and the remaining 5 nested case control studies investigated the association between serum folate levels and the risk of prostate cancer for a total of 9810 individuals, between 321 and 6000 blood samples were included in each study, and follow-up periods ranged from 4.9 to 15.7 years. Furthermore, serum folate level was measured on a non-fasting sample obtained at entry to the study in all included studies. One study was conducted in the United States, 2 were performed in Australia, and the remaining 7 studies [7,8,11–13.15,16] were conducted in Europe. Study quality was assessed using the NOS system. In this study, we considered a study with a score of 8 or 9 as being of high quality. Overall, three studies had a score of 9, four studies had a score of 8, two studies had a score of 7, and one study had a score of 6.
Dietary Folate Intake and the Risk of Prostate Cancer
After pooling the included studies, the summary RR illustrated that a high dietary folate intake was not associated with prostate cancer risk (RR = 1.02; 95% CI = 0.95–1.09; P = 0.598, Figure 2A), and no evidence of heterogeneity was observed (I = 0.0%; P = 0.959). The findings of the dose–response meta-analysis also suggested no association between the risk of prostate cancer and a 100 μg/day increment of dietary folate intake (RR = 1.01; 95% CI = 0.99–1.02; P = 0.433, [I = 0.0%; P = 0.784], Figure 2B). As a result, a sensitivity analysis was conducted, and after each study was sequentially excluded from the pooled analysis, the conclusion was not affected by exclusion of any specific study.
(Enlarge Image)
Figure 2.
Relative risk estimates of prostate cancer for high versus low dietary folate intake (A) and per 100 ug/day increment in folate intake for prostate cancer (B).
All studies were included in the dose–response curve between dietary folate intake and the incidence of prostate cancer. As shown in Figure 3A and illustrated by the P value for nonlinearity (P = 0.012), we found evidence of nonlinear relationships between dietary folate intake and the risk of prostate cancer. Dietary folate intake of more than 300 μg per day appeared to be associated with a non-significant reduction in the risk of prostate cancer.
(Enlarge Image)
Figure 3.
Dose-response relations for dietary folate intake (A) and serum folate levels (B).
Serum Folate Levels and the Risk of Prostate Cancer
A total of 5 prospective nest case control studies reported an association between serum folate levels and the risk of prostate cancer. The pooled analysis results for prostate cancer incidence indicated that the comparison of the high versus low categories of serum folate levels was associated with a harmful effect (RR = 1.21; 95% CI = 1.05–1.39; P = 0.008, with no evidence of heterogeneity [I = 0.0%; P = 0.724]; Figure 4A). The dose–response meta-analysis suggested that a 5 nmol/L increment of serum folate levels was associated with increased risk of prostate cancer (RR = 1.04; 95% CI = 1.00–1.07; P = 0.042, with no evidence of heterogeneity [I = 0.0%; P = 0.418], Figure 4B). Furthermore, as shown by the P value of nonlinearity (P = 0.111), there was no evidence of a potential non-linear relationship (Figure 3B).
(Enlarge Image)
Figure 4.
Relative risk estimates of prostate cancer for high versus low serum folate levels (A) and per 5 nmol/L increment in serum folate levels for prostate cancer (B).
Subgroup Analysis
Heterogeneity testing for the analysis identified a P value >0.10 for prostate cancer incidence. We concluded that heterogeneity is not significant in the overall analysis, suggesting that most variation was attributable to chance alone. Subgroup analyses were conducted to evaluate the effect of folate on prostate cancer risk in a specific population. Overall, we noted that a 5 nmol/L increment of serum folate levels was associated with the increased risk of prostate cancer if the duration of the follow-up less than 15 years. No other significant differences in effects were detected between dietary folate intake or serum folate levels and the risk of prostate cancer (Table 2).
Publication Bias
A review of funnel plots could not eliminate the potential for publication bias for prostate cancer (Figure 5). The Egger and Begg test results disclosed no evidence of publication bias for prostate cancer (Egger: P = 0.694 for dietary folate intake and P = 0.181 for serum folate levels; Begg: P = 0.806 for dietary folate intake and P = 1.000 for serum folate levels; Figure 5).
(Enlarge Image)
Figure 5.
Funnel plot for per 100 ug/day increment in dietary folate intake (A) and per 5 nmol/L increment in serum folate levels for prostate cancer (B).