Dietary alpha-linolenic acid intake and prostate cancer risk: A dose-response analysis of observational studies
Abstract Alpha-linolenic acid (ALA) consumption has been linked to risk of prostate cancer theoretically, but the findings were conflicting from observational studies. Results from recent meta-analysis suggested a small risk, moderate protective and no effect of alpha-linolenic acid consumption on prostate cancer risk. However, the relationship, if exists, between alpha-linolenic acid consumption and prostate cancer risk is unclear. Thus, the dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. The results suggested that a significant association was found between alpha- linolenic acid consumption and decreased risk of prostate cancer among subjects consuming 0.2-1.3g of alpha-linolenic acid per day. A potential nonlinear relationship should be assessed before assuming a linear relationship.
Keywords Alpha-linolenic acid; Prostate cancer; Dose-response analysis
We read with great interest the article by Carleton et al.  titled ''Case-control and prospective studies of dietary alpha-linolenic acid intake and prostate cancer risk: a meta-analysis.'' The study failed to confirm an association between dietary ALA intake and prostate cancer risk. However, the findings were inconsistent with the prior meta-analysis by Simon et al.  and Carayol et al.  indicating a small increased risk and weak protective association between dietary ALA intake and prostate, respectively. This is a very important investigation considering the widespread consumption of alpha-linolenic acid and high incidence of prostate cancer. Thus, it is meaningful regarding the exploration of the causes and control of prostate cancer. However, we would like to draw attention to the type of dose-response analysis between alpha-linolenic acid consumption and risk of prostate cancer, because, Simon et al., Carayol et al. and Carleton et al. [1-3]assumed a linear dose relationship without performing a formal test and the dose relationship was not assessed in the meta-analysis, and linear associations in epidemiologic research can rarely be assumed a priori . Besides, categories of alpha- linolenic acid consumption per day differed between studies, which might complicate the interpretation of the pooled results across study populations with different categories. In this respect, a dose-response meta-analysis provides a solution to the problem, from which a summary risk estimate can be derived for a standardized increase and specific exposure values considering alpha-linolenic acid consumption per day.
Studies included in this dose-response analysis must provide the following information: the number of cases and participants, and odds ratio (OR for case-control studies) and relative risk (RR for cohort studies) estimates with 95 % confidence intervals (CIs) for each category of alpha-linolenic acid consumption were extracted. We extracted the OR or RR (95 % CI) that reflected the greatest degree of control for potential confounders. The median or mean alpha-linolenic acid consumption for each category was assigned to each corresponding OR for every study. If the upper boundary of the highest category was not provided, we assumed that the boundary had the same amplitude as the adjacent category. Detailed information of the included publications is shown in the Table 1 (for case - control studies) and Table 2 (for cohort studies).
A two-stage random-effects dose-response meta-analysis was performed taking into account the between-study heterogeneity proposed by Orsini et al.  to compute the trend from the correlated log OR or RR estimates across categories of alpha-linolenic acid consumption per day. Briefly, a restricted cubic spline model, with four knots at the 5th, 35th, 65th, and 95th percentiles  of the alpha-linolenic acid consumption per day, was estimated using generalized least-square regression taking into account the correlation within each set of published ORs or RR . Then we combined the study-specific estimates using the restricted maximum likelihood method in a multivariate random-effects meta-analysis . A P value for nonlinearity was calculated using the method proposed by Greenland and Longnecker . All statistical analyses were performed with STATA, version 10.0 (Stata Corporation, College Station, Texas, USA). All reported probabilities (p values) were two-sided, with p< 0.05 considered statistically significant.
Dose-response analysis of case-control studies
For case-control studies, data from 6 publications [10-15] with 6 studies were used. A nonlinear relationship was found of alpha-linolenic acid consumption with risk of prostate cancer (P for nonlinearity= 0.0027), and the ORs (95 % CI) of prostate cancer was 0.89 (0.79-1.00), 0.91 (0.78-1.07), 1.25 (1.02-1.54), 1.52 (1.24-1.88), and 1.74 (1.29-2.35) for 0.4, 1.0, 1.6, 2.1, and 2.5 grams per day (Fig. 1).
Dose-response analysis of cohort studies
For cohort studies, data from 5 publications [16-20] with 5 studies were used. The departure from nonlinear relationship was not significant (P for nonlinearity = 0.7488), and the RRs (95 % CI) of prostate cancer was 0.97 (0.94-1.00), 0.96 (0.93-0.99), 0.95 (0.87-1.04), 0.95 (0.86- 1.05), and 0.94 (0.84-1.06) for 1.0, 1.3, 1.7, 2.0, and 2.3 grams per day (Fig. 2).
Dose-response analysis of all observational studies
For case-control and cohort studies, data from 11 publications [10- 20] with 11 studies were used. A nonlinear relationship was found of alpha -linolenic acid consumption with risk of prostate cancer (P for nonlinearity= 0.0132), and the ORs (95 % CI) of prostate cancer was 0.93 (0.89-0.98), 0.88 (0.81-0.96), 0.87 (0.80-0.95), 0.91 (0.85-0.97), 0.98 (0.91-1.06), 1.00 (0.92-1.09), and 1.00 (0.91-1.10) for 0.4, 0.7, 1.0, 1.3, 1.7, 2.0, and 2.3 grams per day (Fig. 3).
Overall, a significant association was found between alpha-linolenic acid consumption and decreased risk of prostate cancer among subjects consuming 0.2-1.3 grams of alpha-linolenic acid per day. Besides, consuming 1.0 gram of alpha-linolenic acid per day can bring us the strongest protective effect of prostate cancer risk. A potential nonlinear relationship should be assessed before assuming a linear relationship, which is not always the case in epidemiologic research and more studies are required to confirm this relationship.
All above mentioned 2 tables and 3 figures can be provided if they were needed.
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