DOI 10.1212/WNL.

0000000000000551
published online June 11, 2014 Neurology
Zhizhong Zhang, Gelin Xu, Fang Yang, et al.
Quantitative analysis of dietary protein intake and stroke risk
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ARTICLES
Zhizhong Zhang, MD,
PhD*
Gelin Xu, MD, PhD*
Fang Yang, MD, PhD
Wusheng Zhu, MD, PhD
Xinfeng Liu, MD, PhD
Correspondence to
Dr. Liu:
xfliu2@vip.163.com
Editorial, page 13
Supplemental data
at Neurology.org
Quantitative analysis of dietary protein
intake and stroke risk
ABSTRACT
Objective: To performa meta-analysis of prospective studies to evaluate the relation between die-
tary 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 0.660.99). 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 0.500.99). 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;83:17
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
More-
over, 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 objec-
tives: (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 eval-
uate the potential dose-response pattern between dietary protein intake and risk of stroke.
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 cer-
ebrovascular 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 pro-
tein, 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 1
2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Published Ahead of Print on June 11, 2014 as 10.1212/WNL.0000000000000551
Data extraction and quality assessment. We extracted the
following data for each study: the first authors last name, publi-
cation year, study location, age, sex, sample size, length of follow-
up, 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
Scale
5
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 I
2
statistic.
6
We calculated the pooled risk esti-
mates 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 meta-
regression model to explore the possible heterogeneity among
studies. We also used the between-study variance (t
2
) to
quantify the degree of heterogeneity and the percentage of t
2
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 pro-
tein 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
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 Longnecker
9
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 bound-
ary had the same amplitude as the nearest category. We exam-
ined 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 statis-
tically significant.
RESULTS Literature search and study characteristics.
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
studies
1319
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 pro-
tein 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 which
16,18,19
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.
Figure 1 Flowchart of study selection
CI 5 confidence interval; OR 5 odds ratio; RR 5 relative risk.
2 Neurology 83 July 1, 2014
2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Stratifying analysis. In the subgroup analyses by stroke
subtype, dietary protein intake showed a protective effect
for intracerebral hemorrhage (table 2). Stratifying by pro-
tein 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.
1316,19
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 het-
erogeneity. When we omitted this study, the combined
RR was 0.75 (95% CI 0.610.91) with marginal het-
erogeneity (p 5 0.125, I
2
5 42.0%). Hypertension
and diabetes were potential confounders of the associ-
ation between dietary protein intake and stroke risk.
The results persisted when we excluded the study
13
that did not adjust for hypertension or diabetes (RR
0.79, 95% CI 0.630.99), with substantial evidence of
heterogeneity (p 5 0.01, I
2
5 67.6%). Further omis-
sion 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 t
2
in the meta-
regression analyses, whereas year of publication
(before and after 2010) could explain 8.01% of the t
2
.
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).
Table 1 Characteristics of the included studies
Ref. Country
Sex and
age, y
No. in
cohort
Follow-
up, y
Protein intake
assessment Outcome
Intake
comparison Adjustment for covariates
13 US M/F 5079 859 12 24-h dietary recall Fatal stroke Continuous
variable
Age, sex, potassium, and calories
14 US F 3459 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 4069 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 3589 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 4075 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 B
6
, vitamin B
12
,
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 5079 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 4983 34,670 10.4 FFQ Fatal/nonfatal
stroke
Quintile (V vs I) Age, combination of smoking status and pack-
years 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
Abbreviations: BMI 5 body mass index; FFQ 5 food frequency questionnaire; MI 5 myocardial infarction; US 5 United States.
Neurology 83 July 1, 2014 3
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DISCUSSION In the past 2 decades, the role of die-
tary 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 pressurelowering 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 cho-
lesterol, and nonhigh-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, replac-
ing intake of other potentially harmful foods.
In our study, the reduced risk of stroke was more evi-
dent for animal protein than vegetable protein. A possi-
ble 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 dif-
ficult 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 studies
15,16
and one study
17
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 con-
duct subgroup analyses to explore sources of hetero-
geneity, 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
Figure 2 Forest plot of cohort studies examining dietary protein intake and stroke risk
CI 5 confidence interval; RR 5 relative risk.
4 Neurology 83 July 1, 2014
2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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, cau-
tion with interpretation of data is necessary. Dietary
protein intake tends to be associated with other
nutrients that may prevent stroke, such as potassi-
um,
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 adjust-
ments 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 die-
tary 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 ques-
tionnaire. This will inevitably lead to some misclassi-
fication of dietary exposures. Only 2 studies in this
meta-analysis updated the information about diet
during follow-up.
14,17
Misclassification of dietary pro-
tein 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.
Figure 3 Dose-response relationship between dietary protein intake and stroke
risk
Table 2 Stratification analyses of dietary protein intake and stroke risk
Group No. of studies RR (95% CI)
Heterogeneity test
x
2
p I
2
, %
Total stroke 7 0.80 (0.660.99) 15.44 0.017 61.1
Ischemic stroke 4 0.82 (0.651.04) 9.47 0.024 68.3
Intracerebral hemorrhage 3 0.57 (0.390.85) 0.29 0.866 0.0
Subarachnoid hemorrhage 2 0.79 (0.471.33) 0.11 0.738 0.0
Protein type
Animal protein 5 0.71 (0.500.99) 13.07 0.011 69.4
Vegetable protein 5 0.88 (0.761.02) 1.17 0.884 0.0
Geographic region
United States 4 0.91 (0.821.00) 7.44 0.059 59.7
Japan 2 0.49 (0.280.83) 0.35 0.557 0.0
Sweden 1 0.74 (0.610.90)
History of hypertension
Yes 2 0.57 (0.400.80) 0.05 0.827 0.0
No 2 0.76 (0.580.99) 3.81 0.051 73.8
Sex
Male 1 1.14 (0.901.44)
Female 3 0.83 (0.750.92) 4.55 0.103 56.1
Quality score
8 stars 4 0.88 (0.681.15) 8.64 0.035 65.3
>8 stars 3 0.71 (0.590.86) 2.25 0.325 11.1
Abbreviations: CI 5 confidence interval; RR 5 relative risk.
Neurology 83 July 1, 2014 5
2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Therefore, in addition to assessing the dietary expo-
sure at enrollment, further studies should update the
assessment of dietary exposure periodically during the
follow-up (e.g., every 24 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 reduc-
tion 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 well-
described dietary changes, as recommended by guide-
lines for stroke prevention and treatment. To date,
large-scale, randomized, controlled trials, which pro-
vide the strongest evidence for establishing a causation,
have not been implemented to directly assess the effect
of protein intake on stroke risk. Considering the com-
pelling evidence from our study, such trials are antic-
ipated 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.
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 revi-
sion 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.
STUDY FUNDING
Supported by the National Natural Science Foundation of China
(31200938, 81220108008), and the Natural Science Foundation of Jin-
ling Hospital (2012009). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the
manuscript.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received November 20, 2013. Accepted in final form February 6, 2014.
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DOI 10.1212/WNL.0000000000000551
published online June 11, 2014 Neurology
Zhizhong Zhang, Gelin Xu, Fang Yang, et al.
Quantitative analysis of dietary protein intake and stroke risk
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