Quantitative analysis of dietary protein intake and stroke risk Zhizhong Zhang, Gelin Xu, Fang Yang, et al. Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000551 This information is current as of June 11, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/06/11/WNL.0000000000000551.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
ARTICLES
Published Ahead of Print on June 11, 2014 as 10.1212/WNL.0000000000000551
Zhizhong Zhang, MD, PhD* Gelin Xu, MD, PhD* Fang Yang, MD, PhD Wusheng Zhu, MD, PhD Xinfeng Liu, MD, PhD
Correspondence to Dr. Liu: [email protected]
Quantitative analysis of dietary protein intake and stroke risk
ABSTRACT
Objective: To perform a meta-analysis of prospective studies to evaluate the relation between dietary protein intake and stroke risk.
Methods: Relevant studies were identified by searching PubMed and Embase through November 2013, and by reviewing the reference lists of retrieved articles. We included prospective cohort studies that reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between dietary protein intake and stroke risk. Results: The meta-analysis included 7 prospective studies involving 254,489 participants. The pooled RR of stroke for the highest compared with the lowest dietary protein intake was 0.80 (95% CI 0.66–0.99). Dose-response analysis indicated that a 20-g/d increment in dietary protein intake was associated with a 26% reduction in stroke risk. Stratifying by protein type, the RR of stroke for animal protein was 0.71 (95% CI 0.50–0.99). Sensitivity analysis restricted to studies with control for common risk factors yielded similar results, and omission of any single study did not change the overall result. Conclusion: These findings suggest that moderate dietary protein intake may lower the risk of stroke. Neurology® 2014;83:1–7 GLOSSARY CI 5 confidence interval; RR 5 relative risk.
Stroke is a major cause of death and permanent disability worldwide.1 Primary prevention of stroke is therefore of utmost importance. Lifestyle factors have important roles in the prevention of stroke, among which dietary protein intake has received great interest. Studies have shown that dietary protein may reduce stroke risk via its favorable effects on blood pressure.2,3 Moreover, an animal study on stroke-prone spontaneously hypertensive rats indicated that rats with a high-protein diet had a delayed onset of stroke.4 Since the 1980s, many studies have investigated the association between dietary protein intake and risk of stroke. However, the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis of prospective cohort studies with the following objectives: (1) to summarize the epidemiologic evidence on the association between dietary protein intake and stroke risk; (2) to examine the dietary protein intake in relation to the risk of stroke according to stroke subtype, protein type, and characteristics of study population; and (3) to evaluate the potential dose-response pattern between dietary protein intake and risk of stroke.
Editorial, page 13 Supplemental data at Neurology.org
METHODS Literature search and selection. We conducted the literature search on PubMed and Embase through November 2013 using the key words “protein intake” combined with “stroke,” “cerebrovascular disease,” “cerebrovascular disorder,” and “cerebrovascular accident.” Moreover, we reviewed the reference lists of retrieved articles to identify additional relevant studies. We included studies if they met the following criteria: (1) prospective design; (2) the exposure of interest was intake of dietary protein, including total protein, animal protein, and vegetable protein; (3) the outcome of interest was fatal/nonfatal stroke and stroke subtypes; and (4) reported the relative risk (RR) and the corresponding 95% confidence interval (CI). Three authors (Z.Z., G.X., and X.L.) independently evaluated the retrieved studies according to the selection criteria. Discrepancies among the 3 reviewers were resolved by consensus. *These authors contributed equally to this work. From the Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
Figure 1
examine how the various exclusion criteria affect the overall results. We also evaluated the influence of a single study on the overall risk estimate by deleting each study in turn. In the dose-response meta-analysis, we adopted the method proposed by Greenland and Longnecker9 and Orsini et al.10 to compute the trend from the correlated log RR estimates across categories of protein intake. For every study, the median or mean protein intake for each category was assigned to each corresponding RR. When the study did not provide the median or mean intake per category, we assigned the midpoint of the upper and lower boundaries in every category as the average intake. If the study did not report the upper or lower boundary for the highest and lowest category, we assumed that the boundary had the same amplitude as the nearest category. We examined a potential nonlinear relationship between protein intake and stroke risk by modeling protein intake using restricted cubic splines with 3 knots at percentiles 25%, 50%, and 75% of the distribution.11 We calculated the p value for nonlinearity by testing the null hypothesis that the coefficient of the second spline is equal to 0. Moreover, we assessed publication bias using the Egger test.12 We used STATA version 12.0 (StataCorp, College Station, TX) for the statistical analyses and considered p , 0.05 as statistically significant.
Flowchart of study selection
RESULTS Literature search and study characteristics.
CI 5 confidence interval; OR 5 odds ratio; RR 5 relative risk.
Data extraction and quality assessment. We extracted the following data for each study: the first author’s last name, publication year, study location, age, sex, sample size, length of followup, protein intake assessment and comparison method, RR from the most fully adjusted model for the highest compared with the lowest dietary protein intake and the corresponding 95% CI, and covariates adjusted for in the multivariate analysis. We used a 9-star system based on the Newcastle-Ottawa Scale5 to assess the study quality in this meta-analysis. The full score was 9 stars, and the high-quality study was defined as a study with .8 awarded stars. Statistical analysis. We extracted the RRs or hazard ratios from the selected studies and computed their standard errors from the respective CIs. We evaluated the heterogeneity among studies with the Q and I2 statistic.6 We calculated the pooled risk estimates using either fixed-effects models or, in the presence of heterogeneity, random-effects models.7 In addition, we examined the variables of geographic area, sample size, length of follow-up, publication year, and quality score in a metaregression model to explore the possible heterogeneity among studies. We also used the between-study variance (t2) to quantify the degree of heterogeneity and the percentage of t2 to depict the level of explained heterogeneity of the variables.8 Moreover, we conducted subgroup analyses according to stroke subtype, protein type, geographic region, history of hypertension, sex, and quality score to evaluate the potential effect modification of these variables on the results. Because characteristics of cohorts, assessment methods of protein intake and endpoint, and adjustments for confounding factors were not consistent among studies, we further performed sensitivity analysis to explore possible explanations for heterogeneity and to 2
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The search strategy yielded 236 entries. After exclusion of studies that did not fulfill the inclusion criteria, 10 remaining articles seemed to be relevant for this meta-analysis (figure 1). We further excluded 4 of these 10 articles for the following reasons: review (n 5 2), and no RR or 95% CI reported (n 5 2). We included one additional article from the reference review. Finally, our present meta-analysis included 7 prospective studies13–19 involving 254,489 participants. Table 1 shows the characteristics of the 7 studies. Four studies were conducted in the United States, 2 in Japan, and one in Sweden. The length of follow-up ranged from 10.4 to 18 years, with a median of 14 years. The cohort sizes ranged from 859 to 85,764 (total 254,489). Four studies assessed the dietary protein intake by food frequency questionnaire and 3 studies by 24-hour dietary recall. The quality scores of each of the included studies are shown in table e-1 on the Neurology® Web site at Neurology.org. The quality scores ranged from 7 to 9, and the median score was 8. Protein intake and stroke risk. Figure 2 shows the multivariable-adjusted RRs for each study and the combined RR for the highest vs the lowest categories of dietary protein intake. For the 7 studies, 6 showed that protein intake was associated with decreased risk of stroke, 3 of which16,18,19 were statistically significant. Only one study showed an opposite trend.17 Overall, compared with subjects in the lowest dietary protein intake, those in the highest had a 20% (95% CI 1%– 34%) lower risk of stroke after adjustment for other risk factors.
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Table 1
Characteristics of the included studies
Ref.
Sex and Country age, y
No. in cohort
Followup, y
Protein intake assessment
Outcome
Intake comparison
13
US
M/F 50–79
859
12
24-h dietary recall
Fatal stroke
Continuous variable
Age, sex, potassium, and calories
14
US
F 34–59
85,764
14
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, smoking, time interval, BMI, alcohol, menopausal status and postmenopausal hormone use, exercise, aspirin, multivitamin use, vitamin E use, n-3 fatty acid, calcium, histories of hypertension, diabetes, high cholesterol levels, total energy intake, cholesterol, fat, and protein
15
Japan
M/F 40–69
4,775
14
24-h dietary recall
Fatal/nonfatal stroke
Quartile (IV vs I)
Age, sex, quartiles of total energy intake and BMI, hypertension, diabetes, serum total cholesterol, smoking, ethanol, and menopausal status
16
Japan
M/F 35–89
3,731
14
24-h diary
Fatal stroke
Tertile (III vs I)
Age, sex, radiation dose, city, BMI, smoking status, alcohol habits, and medical history of hypertension and diabetes
17
US
M 40–75
43,960
18
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, quintiles of percentage of energy from saturated fat, monounsaturated fat, polyunsaturated fat, trans fat, quintiles of calories, fiber, folate, vitamin B6, vitamin B12, potassium, vitamin C, magnesium, total omega-3 fatty acids, glycemic index, physical activity, family history of MI, BMI, smoking, alcohol, multivitamin use, hypertension, hypercholesterolemia, and diabetes
18
US
F 50–79
80,730
12
FFQ
Fatal/nonfatal stroke
Continuous variable
Ethnicity, education, history of cardiovascular disease, family history of premature cardiovascular disease, smoking status, hypertension, treated diabetes, statin use, aspirin use, prior hormone use, and recreational physical activity
19
Sweden
F 49–83
34,670
10.4
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, combination of smoking status and packyears of smoking, education, BMI, total physical activity, history of hypertension and diabetes, aspirin use, family history of MI, intakes of total energy, alcohol, calcium, cholesterol, total fat, fruits, and vegetables
Adjustment for covariates
Abbreviations: BMI 5 body mass index; FFQ 5 food frequency questionnaire; MI 5 myocardial infarction; US 5 United States.
Stratifying analysis. In the subgroup analyses by stroke subtype, dietary protein intake showed a protective effect for intracerebral hemorrhage (table 2). Stratifying by protein type, animal protein and vegetable protein intake could lower risk of stroke by 29% and 12%, respectively (figure 2 and table 2). Stratifying by sex, the associations between dietary protein intake and risk of stroke were stronger in females than in males (table 2). We also observed the protective effect of dietary protein intake in high-quality studies (.8 stars). Dose-response meta-analysis. We next assessed the dose-response relationship between protein intake and risk of stroke. The dose-response analysis included 5 studies.13–16,19 We observed no evidence of a nonlinear relationship between dietary protein intake and stroke risk (p for nonlinearity 5 0.93). The dose-response analysis indicated that the risk of stroke decreased by 26% (RR 0.74, 95% CI 0.65– 0.84; figure 3) for every 20-g/d increment in total protein intake. Sensitivity analyses. We conducted sensitivity analyses to explore potential sources of heterogeneity in the association between dietary protein intake and stroke
risk and to examine the influence of various exclusion criteria on the overall risk estimate. We found that the study by Preis et al.17 accounted for the observed heterogeneity. When we omitted this study, the combined RR was 0.75 (95% CI 0.61–0.91) with marginal heterogeneity (p 5 0.125, I2 5 42.0%). Hypertension and diabetes were potential confounders of the association between dietary protein intake and stroke risk. The results persisted when we excluded the study13 that did not adjust for hypertension or diabetes (RR 0.79, 95% CI 0.63–0.99), with substantial evidence of heterogeneity (p 5 0.01, I2 5 67.6%). Further omission of any single study did not materially alter the overall combined RR, with a range from 0.73 to 0.85. Meta-regression. We used meta-regression analysis to explore the potential sources of heterogeneity. We found that length of follow-up (#14 vs .14 years) alone could explain 45.46% of the t2 in the metaregression analyses, whereas year of publication (before and after 2010) could explain 8.01% of the t2. Publication bias. Visual inspection of the funnel plot
did not identify remarkable asymmetry. Egger test also showed no evidence of publication bias (p 5 0.24). Neurology 83
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Figure 2
Forest plot of cohort studies examining dietary protein intake and stroke risk
CI 5 confidence interval; RR 5 relative risk.
DISCUSSION In the past 2 decades, the role of dietary protein in the development of stroke has been increasingly recognized. Our meta-analysis containing 254,489 participants provides evidence that protein intake is independently associated with a decreased risk of stroke. The protective effect of dietary protein against risk of stroke may in part be attributable to its blood pressure–lowering effect. A study has indicated that a higher intake of the amino acid arginine could enhance levels of the endogenous vasodilator nitric oxide and reduce blood pressure.20 A randomized trial has also shown that substitution of dietary carbohydrates with protein reduced blood pressure.21 Because hypertension is a crucial risk factor for stroke, it is plausible that a higher intake of dietary protein may reduce stroke risk. In addition to lowering blood pressure, the protein diet also significantly lowered triglycerides, total cholesterol, and non–high-density lipoprotein cholesterol, compared with the carbohydrate diet.21 An animal study indicated that a moderate increase in dietary crude protein content could reduce fat deposition.22 Also, a study has shown that doenjang, a fermented soybean paste that is a rich source of protein, resulted in a 25.4% reduction in adipocyte size compared with no supplementation.23 Moreover, dietary protein may also decrease stroke risk via a substitution effect, replacing intake of other potentially harmful foods. 4
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In our study, the reduced risk of stroke was more evident for animal protein than vegetable protein. A possible interpretation is that the range of protein intake between the highest and lowest categories was narrower for vegetable protein (15.6 g/d) than for animal protein (34.7 g/d) in our meta-analysis, which made it more difficult to observe a statistically significant association. Among different protein sources, fish consumption has been associated with decreased risk of stroke,24 whereas red meat consumption has been associated with increased stroke risk.25,26 In addition, compared with Westerners, Asians tend to eat more fish and less red meat. In our meta-analysis, decreased stroke risk was observed in 2 Japanese studies15,16 and one study17 in which fish was the primary source of animal protein. These results indicated that stroke risk may be reduced by replacing red meat with other protein sources such as fish. Meta-analysis is an important method to reveal trends that might not be evident in a single study. With the accumulative evidence, we were able to enhance the precision of the risk estimates and conduct subgroup analyses to explore sources of heterogeneity, hence increasing the clinical relevance of our findings. In addition, all included studies adopted a prospective cohort design, which minimized the possibility of recall and selection biases. Moreover, the presence of a dose-response relationship further
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Table 2
Stratification analyses of dietary protein intake and stroke risk Heterogeneity test
Group
No. of studies
RR (95% CI)
x2
p
I2, %
Total stroke
7
0.80 (0.66–0.99)
15.44
0.017
61.1
Ischemic stroke
4
0.82 (0.65–1.04)
9.47
0.024
68.3
Intracerebral hemorrhage
3
0.57 (0.39–0.85)
0.29
0.866
0.0
Subarachnoid hemorrhage
2
0.79 (0.47–1.33)
0.11
0.738
0.0
Animal protein
5
0.71 (0.50–0.99)
13.07
0.011
69.4
Vegetable protein
5
0.88 (0.76–1.02)
1.17
0.884
0.0
United States
4
0.91 (0.82–1.00)
7.44
0.059
59.7
Japan
2
0.49 (0.28–0.83)
0.35
0.557
0.0
Sweden
1
0.74 (0.61–0.90)
—
—
—
Yes
2
0.57 (0.40–0.80)
0.05
0.827
0.0
No
2
0.76 (0.58–0.99)
3.81
0.051
73.8
Male
1
1.14 (0.90–1.44)
—
—
—
Female
3
0.83 (0.75–0.92)
4.55
0.103
56.1
£8 stars
4
0.88 (0.68–1.15)
8.64
0.035
65.3
>8 stars
3
0.71 (0.59–0.86)
2.25
0.325
11.1
Protein type
Geographic region
History of hypertension
Sex
Quality score
Abbreviations: CI 5 confidence interval; RR 5 relative risk.
strengthened the association of dietary protein intake with risk of stroke. This meta-analysis also had several limitations. First, as a meta-analysis of observational studies, the possibility that other factors may account for the observed association cannot be excluded. Thus, caution with interpretation of data is necessary. Dietary protein intake tends to be associated with other
Figure 3
Dose-response relationship between dietary protein intake and stroke risk
nutrients that may prevent stroke, such as potassium,27,28 magnesium,29 and dietary fiber.30 However, the association between protein intake and risk of stroke persisted when we confined the analysis to studies that adjusted for these risk factors. Second, there was substantial heterogeneity among included studies, which was not surprising given the differences in population characteristics, sample sizes, and adjustments for potential confounders. Our subgroup and sensitivity analyses showed that studies conducted in females, and with a higher quality score, provided homogeneous results. Third, misclassification of dietary exposures and the long interval between exposure and outcome may affect our meta-analysis results, particularly in some observational studies in which diet was assessed at enrollment (at one time point) and was self-reported through a food frequency questionnaire. This will inevitably lead to some misclassification of dietary exposures. Only 2 studies in this meta-analysis updated the information about diet during follow-up.14,17 Misclassification of dietary protein intake may have been present in the remaining studies that assessed diet at baseline only, which could lead to an underestimation of the true association between dietary protein intake and stroke risk. Neurology 83
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Therefore, in addition to assessing the dietary exposure at enrollment, further studies should update the assessment of dietary exposure periodically during the follow-up (e.g., every 2–4 years). Stroke is a leading cause of death and disability worldwide. The association between dietary protein intake and stroke risk remains inconsistent. Findings from our study aimed at addressing this issue and resolving the inconsistency are both timely and crucial. According to the result of our meta-analysis, a 20-g/d increment in protein intake was associated with a reduction in the risk of stroke of 26%. This risk reduction would be translated into a reduction of 1,482,000 stroke deaths every year worldwide and is expected to produce overall health benefits by decreasing the level of disability.31 Protein intake may be increased by welldescribed dietary changes, as recommended by guidelines for stroke prevention and treatment. To date, large-scale, randomized, controlled trials, which provide the strongest evidence for establishing a causation, have not been implemented to directly assess the effect of protein intake on stroke risk. Considering the compelling evidence from our study, such trials are anticipated to draw definitive conclusions. In summary, this meta-analysis of prospective studies suggests that moderate dietary protein intake may lower the risk of stroke. Further experimental studies are needed to confirm the beneficial effects of protein intake.
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15. AUTHOR CONTRIBUTIONS Study concept and design: Z.Z. and X.L. Data collection: Z.Z., G.X., and X.L. Statistical analyses: Z.Z. and G.X. Manuscript writing: Z.Z. Interpretation of results: Z.Z., G.X., F.Y., W.Z., and X.L. Critical revision of the manuscript: Z.Z., G.X., and X.L. X.L. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
16.
17. STUDY FUNDING Supported by the National Natural Science Foundation of China (31200938, 81220108008), and the Natural Science Foundation of Jinling Hospital (2012009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
18.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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19.
Received November 20, 2013. Accepted in final form February 6, 2014.
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Quantitative analysis of dietary protein intake and stroke risk Zhizhong Zhang, Gelin Xu, Fang Yang, et al. Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000551 This information is current as of June 11, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/06/11/WNL.00000 00000000551.full.html
Supplementary Material
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
ARTICLES
Published Ahead of Print on June 11, 2014 as 10.1212/WNL.0000000000000551
Zhizhong Zhang, MD, PhD* Gelin Xu, MD, PhD* Fang Yang, MD, PhD Wusheng Zhu, MD, PhD Xinfeng Liu, MD, PhD
Correspondence to Dr. Liu: [email protected]
Quantitative analysis of dietary protein intake and stroke risk
ABSTRACT
Objective: To perform a meta-analysis of prospective studies to evaluate the relation between dietary protein intake and stroke risk.
Methods: Relevant studies were identified by searching PubMed and Embase through November 2013, and by reviewing the reference lists of retrieved articles. We included prospective cohort studies that reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between dietary protein intake and stroke risk. Results: The meta-analysis included 7 prospective studies involving 254,489 participants. The pooled RR of stroke for the highest compared with the lowest dietary protein intake was 0.80 (95% CI 0.66–0.99). Dose-response analysis indicated that a 20-g/d increment in dietary protein intake was associated with a 26% reduction in stroke risk. Stratifying by protein type, the RR of stroke for animal protein was 0.71 (95% CI 0.50–0.99). Sensitivity analysis restricted to studies with control for common risk factors yielded similar results, and omission of any single study did not change the overall result. Conclusion: These findings suggest that moderate dietary protein intake may lower the risk of stroke. Neurology® 2014;83:1–7 GLOSSARY CI 5 confidence interval; RR 5 relative risk.
Stroke is a major cause of death and permanent disability worldwide.1 Primary prevention of stroke is therefore of utmost importance. Lifestyle factors have important roles in the prevention of stroke, among which dietary protein intake has received great interest. Studies have shown that dietary protein may reduce stroke risk via its favorable effects on blood pressure.2,3 Moreover, an animal study on stroke-prone spontaneously hypertensive rats indicated that rats with a high-protein diet had a delayed onset of stroke.4 Since the 1980s, many studies have investigated the association between dietary protein intake and risk of stroke. However, the results of these studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis of prospective cohort studies with the following objectives: (1) to summarize the epidemiologic evidence on the association between dietary protein intake and stroke risk; (2) to examine the dietary protein intake in relation to the risk of stroke according to stroke subtype, protein type, and characteristics of study population; and (3) to evaluate the potential dose-response pattern between dietary protein intake and risk of stroke.
Editorial, page 13 Supplemental data at Neurology.org
METHODS Literature search and selection. We conducted the literature search on PubMed and Embase through November 2013 using the key words “protein intake” combined with “stroke,” “cerebrovascular disease,” “cerebrovascular disorder,” and “cerebrovascular accident.” Moreover, we reviewed the reference lists of retrieved articles to identify additional relevant studies. We included studies if they met the following criteria: (1) prospective design; (2) the exposure of interest was intake of dietary protein, including total protein, animal protein, and vegetable protein; (3) the outcome of interest was fatal/nonfatal stroke and stroke subtypes; and (4) reported the relative risk (RR) and the corresponding 95% confidence interval (CI). Three authors (Z.Z., G.X., and X.L.) independently evaluated the retrieved studies according to the selection criteria. Discrepancies among the 3 reviewers were resolved by consensus. *These authors contributed equally to this work. From the Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Jiangsu Province, China. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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Figure 1
examine how the various exclusion criteria affect the overall results. We also evaluated the influence of a single study on the overall risk estimate by deleting each study in turn. In the dose-response meta-analysis, we adopted the method proposed by Greenland and Longnecker9 and Orsini et al.10 to compute the trend from the correlated log RR estimates across categories of protein intake. For every study, the median or mean protein intake for each category was assigned to each corresponding RR. When the study did not provide the median or mean intake per category, we assigned the midpoint of the upper and lower boundaries in every category as the average intake. If the study did not report the upper or lower boundary for the highest and lowest category, we assumed that the boundary had the same amplitude as the nearest category. We examined a potential nonlinear relationship between protein intake and stroke risk by modeling protein intake using restricted cubic splines with 3 knots at percentiles 25%, 50%, and 75% of the distribution.11 We calculated the p value for nonlinearity by testing the null hypothesis that the coefficient of the second spline is equal to 0. Moreover, we assessed publication bias using the Egger test.12 We used STATA version 12.0 (StataCorp, College Station, TX) for the statistical analyses and considered p , 0.05 as statistically significant.
Flowchart of study selection
RESULTS Literature search and study characteristics.
CI 5 confidence interval; OR 5 odds ratio; RR 5 relative risk.
Data extraction and quality assessment. We extracted the following data for each study: the first author’s last name, publication year, study location, age, sex, sample size, length of followup, protein intake assessment and comparison method, RR from the most fully adjusted model for the highest compared with the lowest dietary protein intake and the corresponding 95% CI, and covariates adjusted for in the multivariate analysis. We used a 9-star system based on the Newcastle-Ottawa Scale5 to assess the study quality in this meta-analysis. The full score was 9 stars, and the high-quality study was defined as a study with .8 awarded stars. Statistical analysis. We extracted the RRs or hazard ratios from the selected studies and computed their standard errors from the respective CIs. We evaluated the heterogeneity among studies with the Q and I2 statistic.6 We calculated the pooled risk estimates using either fixed-effects models or, in the presence of heterogeneity, random-effects models.7 In addition, we examined the variables of geographic area, sample size, length of follow-up, publication year, and quality score in a metaregression model to explore the possible heterogeneity among studies. We also used the between-study variance (t2) to quantify the degree of heterogeneity and the percentage of t2 to depict the level of explained heterogeneity of the variables.8 Moreover, we conducted subgroup analyses according to stroke subtype, protein type, geographic region, history of hypertension, sex, and quality score to evaluate the potential effect modification of these variables on the results. Because characteristics of cohorts, assessment methods of protein intake and endpoint, and adjustments for confounding factors were not consistent among studies, we further performed sensitivity analysis to explore possible explanations for heterogeneity and to 2
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The search strategy yielded 236 entries. After exclusion of studies that did not fulfill the inclusion criteria, 10 remaining articles seemed to be relevant for this meta-analysis (figure 1). We further excluded 4 of these 10 articles for the following reasons: review (n 5 2), and no RR or 95% CI reported (n 5 2). We included one additional article from the reference review. Finally, our present meta-analysis included 7 prospective studies13–19 involving 254,489 participants. Table 1 shows the characteristics of the 7 studies. Four studies were conducted in the United States, 2 in Japan, and one in Sweden. The length of follow-up ranged from 10.4 to 18 years, with a median of 14 years. The cohort sizes ranged from 859 to 85,764 (total 254,489). Four studies assessed the dietary protein intake by food frequency questionnaire and 3 studies by 24-hour dietary recall. The quality scores of each of the included studies are shown in table e-1 on the Neurology® Web site at Neurology.org. The quality scores ranged from 7 to 9, and the median score was 8. Protein intake and stroke risk. Figure 2 shows the multivariable-adjusted RRs for each study and the combined RR for the highest vs the lowest categories of dietary protein intake. For the 7 studies, 6 showed that protein intake was associated with decreased risk of stroke, 3 of which16,18,19 were statistically significant. Only one study showed an opposite trend.17 Overall, compared with subjects in the lowest dietary protein intake, those in the highest had a 20% (95% CI 1%– 34%) lower risk of stroke after adjustment for other risk factors.
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Table 1
Characteristics of the included studies
Ref.
Sex and Country age, y
No. in cohort
Followup, y
Protein intake assessment
Outcome
Intake comparison
13
US
M/F 50–79
859
12
24-h dietary recall
Fatal stroke
Continuous variable
Age, sex, potassium, and calories
14
US
F 34–59
85,764
14
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, smoking, time interval, BMI, alcohol, menopausal status and postmenopausal hormone use, exercise, aspirin, multivitamin use, vitamin E use, n-3 fatty acid, calcium, histories of hypertension, diabetes, high cholesterol levels, total energy intake, cholesterol, fat, and protein
15
Japan
M/F 40–69
4,775
14
24-h dietary recall
Fatal/nonfatal stroke
Quartile (IV vs I)
Age, sex, quartiles of total energy intake and BMI, hypertension, diabetes, serum total cholesterol, smoking, ethanol, and menopausal status
16
Japan
M/F 35–89
3,731
14
24-h diary
Fatal stroke
Tertile (III vs I)
Age, sex, radiation dose, city, BMI, smoking status, alcohol habits, and medical history of hypertension and diabetes
17
US
M 40–75
43,960
18
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, quintiles of percentage of energy from saturated fat, monounsaturated fat, polyunsaturated fat, trans fat, quintiles of calories, fiber, folate, vitamin B6, vitamin B12, potassium, vitamin C, magnesium, total omega-3 fatty acids, glycemic index, physical activity, family history of MI, BMI, smoking, alcohol, multivitamin use, hypertension, hypercholesterolemia, and diabetes
18
US
F 50–79
80,730
12
FFQ
Fatal/nonfatal stroke
Continuous variable
Ethnicity, education, history of cardiovascular disease, family history of premature cardiovascular disease, smoking status, hypertension, treated diabetes, statin use, aspirin use, prior hormone use, and recreational physical activity
19
Sweden
F 49–83
34,670
10.4
FFQ
Fatal/nonfatal stroke
Quintile (V vs I)
Age, combination of smoking status and packyears of smoking, education, BMI, total physical activity, history of hypertension and diabetes, aspirin use, family history of MI, intakes of total energy, alcohol, calcium, cholesterol, total fat, fruits, and vegetables
Adjustment for covariates
Abbreviations: BMI 5 body mass index; FFQ 5 food frequency questionnaire; MI 5 myocardial infarction; US 5 United States.
Stratifying analysis. In the subgroup analyses by stroke subtype, dietary protein intake showed a protective effect for intracerebral hemorrhage (table 2). Stratifying by protein type, animal protein and vegetable protein intake could lower risk of stroke by 29% and 12%, respectively (figure 2 and table 2). Stratifying by sex, the associations between dietary protein intake and risk of stroke were stronger in females than in males (table 2). We also observed the protective effect of dietary protein intake in high-quality studies (.8 stars). Dose-response meta-analysis. We next assessed the dose-response relationship between protein intake and risk of stroke. The dose-response analysis included 5 studies.13–16,19 We observed no evidence of a nonlinear relationship between dietary protein intake and stroke risk (p for nonlinearity 5 0.93). The dose-response analysis indicated that the risk of stroke decreased by 26% (RR 0.74, 95% CI 0.65– 0.84; figure 3) for every 20-g/d increment in total protein intake. Sensitivity analyses. We conducted sensitivity analyses to explore potential sources of heterogeneity in the association between dietary protein intake and stroke
risk and to examine the influence of various exclusion criteria on the overall risk estimate. We found that the study by Preis et al.17 accounted for the observed heterogeneity. When we omitted this study, the combined RR was 0.75 (95% CI 0.61–0.91) with marginal heterogeneity (p 5 0.125, I2 5 42.0%). Hypertension and diabetes were potential confounders of the association between dietary protein intake and stroke risk. The results persisted when we excluded the study13 that did not adjust for hypertension or diabetes (RR 0.79, 95% CI 0.63–0.99), with substantial evidence of heterogeneity (p 5 0.01, I2 5 67.6%). Further omission of any single study did not materially alter the overall combined RR, with a range from 0.73 to 0.85. Meta-regression. We used meta-regression analysis to explore the potential sources of heterogeneity. We found that length of follow-up (#14 vs .14 years) alone could explain 45.46% of the t2 in the metaregression analyses, whereas year of publication (before and after 2010) could explain 8.01% of the t2. Publication bias. Visual inspection of the funnel plot
did not identify remarkable asymmetry. Egger test also showed no evidence of publication bias (p 5 0.24). Neurology 83
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Figure 2
Forest plot of cohort studies examining dietary protein intake and stroke risk
CI 5 confidence interval; RR 5 relative risk.
DISCUSSION In the past 2 decades, the role of dietary protein in the development of stroke has been increasingly recognized. Our meta-analysis containing 254,489 participants provides evidence that protein intake is independently associated with a decreased risk of stroke. The protective effect of dietary protein against risk of stroke may in part be attributable to its blood pressure–lowering effect. A study has indicated that a higher intake of the amino acid arginine could enhance levels of the endogenous vasodilator nitric oxide and reduce blood pressure.20 A randomized trial has also shown that substitution of dietary carbohydrates with protein reduced blood pressure.21 Because hypertension is a crucial risk factor for stroke, it is plausible that a higher intake of dietary protein may reduce stroke risk. In addition to lowering blood pressure, the protein diet also significantly lowered triglycerides, total cholesterol, and non–high-density lipoprotein cholesterol, compared with the carbohydrate diet.21 An animal study indicated that a moderate increase in dietary crude protein content could reduce fat deposition.22 Also, a study has shown that doenjang, a fermented soybean paste that is a rich source of protein, resulted in a 25.4% reduction in adipocyte size compared with no supplementation.23 Moreover, dietary protein may also decrease stroke risk via a substitution effect, replacing intake of other potentially harmful foods. 4
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In our study, the reduced risk of stroke was more evident for animal protein than vegetable protein. A possible interpretation is that the range of protein intake between the highest and lowest categories was narrower for vegetable protein (15.6 g/d) than for animal protein (34.7 g/d) in our meta-analysis, which made it more difficult to observe a statistically significant association. Among different protein sources, fish consumption has been associated with decreased risk of stroke,24 whereas red meat consumption has been associated with increased stroke risk.25,26 In addition, compared with Westerners, Asians tend to eat more fish and less red meat. In our meta-analysis, decreased stroke risk was observed in 2 Japanese studies15,16 and one study17 in which fish was the primary source of animal protein. These results indicated that stroke risk may be reduced by replacing red meat with other protein sources such as fish. Meta-analysis is an important method to reveal trends that might not be evident in a single study. With the accumulative evidence, we were able to enhance the precision of the risk estimates and conduct subgroup analyses to explore sources of heterogeneity, hence increasing the clinical relevance of our findings. In addition, all included studies adopted a prospective cohort design, which minimized the possibility of recall and selection biases. Moreover, the presence of a dose-response relationship further
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Table 2
Stratification analyses of dietary protein intake and stroke risk Heterogeneity test
Group
No. of studies
RR (95% CI)
x2
p
I2, %
Total stroke
7
0.80 (0.66–0.99)
15.44
0.017
61.1
Ischemic stroke
4
0.82 (0.65–1.04)
9.47
0.024
68.3
Intracerebral hemorrhage
3
0.57 (0.39–0.85)
0.29
0.866
0.0
Subarachnoid hemorrhage
2
0.79 (0.47–1.33)
0.11
0.738
0.0
Animal protein
5
0.71 (0.50–0.99)
13.07
0.011
69.4
Vegetable protein
5
0.88 (0.76–1.02)
1.17
0.884
0.0
United States
4
0.91 (0.82–1.00)
7.44
0.059
59.7
Japan
2
0.49 (0.28–0.83)
0.35
0.557
0.0
Sweden
1
0.74 (0.61–0.90)
—
—
—
Yes
2
0.57 (0.40–0.80)
0.05
0.827
0.0
No
2
0.76 (0.58–0.99)
3.81
0.051
73.8
Male
1
1.14 (0.90–1.44)
—
—
—
Female
3
0.83 (0.75–0.92)
4.55
0.103
56.1
£8 stars
4
0.88 (0.68–1.15)
8.64
0.035
65.3
>8 stars
3
0.71 (0.59–0.86)
2.25
0.325
11.1
Protein type
Geographic region
History of hypertension
Sex
Quality score
Abbreviations: CI 5 confidence interval; RR 5 relative risk.
strengthened the association of dietary protein intake with risk of stroke. This meta-analysis also had several limitations. First, as a meta-analysis of observational studies, the possibility that other factors may account for the observed association cannot be excluded. Thus, caution with interpretation of data is necessary. Dietary protein intake tends to be associated with other
Figure 3
Dose-response relationship between dietary protein intake and stroke risk
nutrients that may prevent stroke, such as potassium,27,28 magnesium,29 and dietary fiber.30 However, the association between protein intake and risk of stroke persisted when we confined the analysis to studies that adjusted for these risk factors. Second, there was substantial heterogeneity among included studies, which was not surprising given the differences in population characteristics, sample sizes, and adjustments for potential confounders. Our subgroup and sensitivity analyses showed that studies conducted in females, and with a higher quality score, provided homogeneous results. Third, misclassification of dietary exposures and the long interval between exposure and outcome may affect our meta-analysis results, particularly in some observational studies in which diet was assessed at enrollment (at one time point) and was self-reported through a food frequency questionnaire. This will inevitably lead to some misclassification of dietary exposures. Only 2 studies in this meta-analysis updated the information about diet during follow-up.14,17 Misclassification of dietary protein intake may have been present in the remaining studies that assessed diet at baseline only, which could lead to an underestimation of the true association between dietary protein intake and stroke risk. Neurology 83
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Therefore, in addition to assessing the dietary exposure at enrollment, further studies should update the assessment of dietary exposure periodically during the follow-up (e.g., every 2–4 years). Stroke is a leading cause of death and disability worldwide. The association between dietary protein intake and stroke risk remains inconsistent. Findings from our study aimed at addressing this issue and resolving the inconsistency are both timely and crucial. According to the result of our meta-analysis, a 20-g/d increment in protein intake was associated with a reduction in the risk of stroke of 26%. This risk reduction would be translated into a reduction of 1,482,000 stroke deaths every year worldwide and is expected to produce overall health benefits by decreasing the level of disability.31 Protein intake may be increased by welldescribed dietary changes, as recommended by guidelines for stroke prevention and treatment. To date, large-scale, randomized, controlled trials, which provide the strongest evidence for establishing a causation, have not been implemented to directly assess the effect of protein intake on stroke risk. Considering the compelling evidence from our study, such trials are anticipated to draw definitive conclusions. In summary, this meta-analysis of prospective studies suggests that moderate dietary protein intake may lower the risk of stroke. Further experimental studies are needed to confirm the beneficial effects of protein intake.
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15. AUTHOR CONTRIBUTIONS Study concept and design: Z.Z. and X.L. Data collection: Z.Z., G.X., and X.L. Statistical analyses: Z.Z. and G.X. Manuscript writing: Z.Z. Interpretation of results: Z.Z., G.X., F.Y., W.Z., and X.L. Critical revision of the manuscript: Z.Z., G.X., and X.L. X.L. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
16.
17. STUDY FUNDING Supported by the National Natural Science Foundation of China (31200938, 81220108008), and the Natural Science Foundation of Jinling Hospital (2012009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
18.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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Received November 20, 2013. Accepted in final form February 6, 2014.
20.
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Quantitative analysis of dietary protein intake and stroke risk Zhizhong Zhang, Gelin Xu, Fang Yang, et al. Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000551 This information is current as of June 11, 2014 Updated Information & Services
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