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Whole Grain Intake and Mortality From All Causes,

Cardiovascular Disease, and Cancer


A Meta-Analysis of Prospective Cohort Studies
Geng Zong, PhD; Alisa Gao; Frank B. Hu, MD, PhD; Qi Sun, MD, ScD

Background—Current findings on associations between whole grain (WG) intake and mortality are inconsistent and have
not been summarized by meta-analysis.
Methods and Results—We searched for prospective cohort studies reporting associations between WG intake and mortality
from all causes, cardiovascular disease (CVD), and cancer through February 2016 in Medline, Embase, and clinicaltrials.gov,
and we further included unpublished results from National Health and Nutrition Examination Survey (NHANES) III and
NHANES 1999 to 2004. Fourteen studies were eligible for analysis, which included 786 076 participants, 97 867 total
deaths, 23 957 CVD deaths, and 37 492 cancer deaths. Pooled relative risks comparing extreme WG categories (high versus
low) were 0.84 (95% confidence interval [CI], 0.80–0.88; P<0.001; I2=74%; Pheterogeneity<0.001) for total mortality, 0.82
(95% CI, 0.79–0.85; P<0.001; I2=0%; Pheterogeneity=0.53) for CVD mortality, and 0.88 (95% CI, 0.83–0.94; P<0.001; I2=54%;
Pheterogeneity=0.02) for cancer mortality. Intakes of WG ingredients in dry weight were estimated among studies reporting
relative risks for ≥3 quantitative WG categories, and they were <50 g/d among most study populations. The 2-stage dose-
response random-effects meta-analysis showed monotonic associations between WG intake and mortality (Pnonlinearity>0.05).
For each 16-g/d increase in WG (≈1 serving per d), relative risks of total, CVD, and cancer mortality were 0.93 (95% CI,
0.92–0.94; P<0.001), 0.91 (95% CI, 0.90–0.93; P<0.001), and 0.95 (95% CI, 0.94–0.96; P<0.001), respectively.
Conclusions—Our meta-analysis demonstrated inverse associations of WG intake with total and cause-specific mortality, and
findings were particularly strong and robust for CVD mortality. These findings further support current Dietary Guidelines
for Americans, which recommends at least 3 servings per day of WG intake.  (Circulation. 2016;133:2370-2380.
DOI: 10.1161/CIRCULATIONAHA.115.021101.)
Key Words: diet ◼ meta-analysis [publication type] ◼ mortality ◼ whole grains

W hole grains (WGs) are rich in dietary fiber, vitamins,


minerals, phytochemicals, and other bioactive com-
pounds that may jointly favor long-term health.1,2 Although
meta-analyses of prospective studies have consistently
reported inverse associations between WG intake and type
2 diabetes mellitus,8–11 cardiovascular diseases (CVDs),8,12,13
dietary guidelines around the world have included WGs as an and certain cancers,14–16 which are among the major global
essential component of healthy eating patterns,3 consumption causes of death. However, existing findings on WG intake
is largely below recommendations in the United States and and mortality remain largely inconclusive. Although several
many European countries.4–7 For example, WG intake among studies observed significant inverse associations between WG
US adults remains <1 serving per day, despite the long-time intake and both total and CVD mortality,17–23 others reported
recommendation in Dietary Guidelines for Americans of ≥3 null findings.22,24 To the best of our knowledge, no studies have
servings per day WG intake.4 quantitatively summarized the published literature on associa-
tions of WG intake with total and cause-specific mortality.
Clinical Perspective on p 2380
Therefore, we performed a meta-analysis of prospective
Given the lack of large-scale intervention studies inves- cohort studies on WG intake and risks of total, CVD, and
tigating the effects of WG intake on chronic disease risk, cancer mortality. We estimated WG ingredient intake in dry
well-conducted prospective cohort studies provide the most weight among eligible studies and explored potential dose-
promising evidence on the health benefits of WG. Previous response relationships between WG intake and mortality. In

Received December 21, 2015; accepted May 3, 2016.


From the Departments of Nutrition (G.Z., A.G., F.B.H., Q.S.) and Epidemiology (F.B.H.), Harvard T.H. Chan School of Public Health, Boston, MA;
and Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
(F.B.H., Q.S.).
Guest Editor for this article was Rachel Johnson, PhD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
115.021101/-/DC1.
Correspondence to Qi Sun, MD, ScD, Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115.
E-mail qisun@hsph.harvard.edu
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.021101

2370
Zong et al   Whole Grain Intake, Mortality, and CVD Mortality   2371

addition, we analyzed associations between WG intake and Search and Data Extraction
mortality in 2 National Health and Nutrition Examination Two authors (G.Z. and A.G.) independently screened titles and
Survey (NHANES) populations and included these original abstracts of articles retrieved in the initial search, evaluated the eli-
gibility of articles on the basis of a full text review, and extracted
results in this meta-analysis. data. Differences of opinions were resolved by discussion among
authors to reach consensus. The following data were extracted from
Methods each study: first author’s last name; year of publication; study loca-
tion; study period; follow-up duration; number of participants; age;
Search Strategy amounts of WG ingredient/food intake; methods of diet assessment;
number of deaths from all causes, CVD, or cancer; methods of death
Our study followed the Meta-Analysis of Observational Studies in
confirmation; relative risks (RRs; measured by hazard ratios in all
Epidemiology guidelines.25 A literature search was performed in individual studies) and confidence intervals (CIs) for all WG catego-
Medline, Embase, and clinicaltrials.gov for articles published through ries; and covariates adjusted in multivariable analysis. For studies
February 9, 2015. We combined search terms on exposure (WG and reporting WG ingredient intake, we extracted food items and meth-
its variants and specific cereal grains such as oat, barley, brown rice, ods for WG ingredient calculation.18,19,21–23 For studies reporting WG
and wheat) and outcomes (mortality and cause of death) without lan- food intake, we extracted the definitions of and a list of specific WG
guage restriction. Details of the search strategies are shown in the foods.17,20,24,26–28
online-only Data Supplement. Reference lists of retrieved articles To evaluate potential dose-response relationships, we further
were scanned manually for additional studies. extracted numbers of cases, numbers of participants, and median
intakes in each WG category from studies that reported RRs (95%
CIs) for ≥3 quantitative WG categories.18,20,21,23 If numbers of partici-
Eligibility pants and cases were not provided, we used the average number of
Candidate articles were included if they met all of the following crite- cases and participants (total participants or cases divided by the num-
ria: They applied a prospective cohort design; the exposure included ber of categories).19,22 When median intake was missing, we approxi-
mated it by using the midpoint of the lower and upper bounds. If
intakes of WG ingredients (with specified methods for calculation)
the highest category was open-ended, we assumed that the highest
or WG foods (with specified food items); and the outcome included category had the same WG intake range as the adjacent category. For
mortality from all causes, CVD, or cancer. For multiple sets of results studies reporting WG as servings per day or analyzing WG foods,
published from the same study population, we used results based on we converted medians into WG ingredients in grams by referring
the longest duration of follow-up. to additional publications or databases that provide WG amounts

Records from PubMed Records from EMBASE Records from clincialtrial.gov


(N=3286) (N=1453) (N=119)

Redundant records (N=796)

Records retrieved for title and abstract review


(N=4062)

Excluded (N=3966)
Reviews/case reports/editorials/commentaries (N=401)
Animal/cell studies (N=739)
Germ cell tumor studies (N=585)
Genetic mutation studies (N=219)
Non-adult populations (N=253)
Not relevant (N=1769)

Records retrieved for full article review


(N=94) Figure 1. Flow diagram of study screening. CVD
indicates cardiovascular disease.
Excluded (N=84)
No whole grain assessments (N=26)
No mortality data (N=38)
Non-prospective study design (N=7)
Multiple results based on the same population (N=5)
Among patients with CVD or cancer (N=3)
Lack of whole grain definition (N=4)
Whole grain reported as continuous variable (N=1)

Included articles Retrieved from reference Unpublished studies


(N=10) (N=1) (N=2)

13 articles with 14 eligible studies


All-cause mortality (N=12)
CVD mortality (N=11)
Cancer mortality (N=9)
2372  Circulation  June 14, 2016

Table 1  Characteristics of Studies Included in the Meta-Analysis


Dietary
Author questionnaire/ WG Death confirmation/
publication year, Sample, n/ assessment/ death code/
location Age, y/ WG calculation if WG food item†/ Cause of death Risk estimate compared to
Ref #, Duration, y reporting ingredients WG dose in each group (number) reference (lowest) group Covariates

Fraser et al17 26 473/ Baseline FFQ/ WG bread/ death certificates, CVD: 0.74 (0.56–0.99) Age, sex, smoking,
1992, US ≥25/ WG food 100% whole-wheat bread used registry and records/ exercise, relative
most often, white bread used ICD/ weight, high blood
6 (1977–1982)
most often. pressure, nuts, beef,
CVD (463)
cheese, fish, coffee,
legumes, and fruits.

Key et al24 10 771/ Baseline FFQ/ WG bread/ death certificates/ All-cause: Age, sex, and smoking
1996, UK 16–79/ WG food Having WG daily, not having WG ICD8, ICD9/ 0.88 (0.78, 0.98);
daily. CHD: 0.85 (0.68, 1.06);
17 (1973–1995) All-cause (2562)
CHD (350) Stroke: 1.08 (0.75, 1.54);
stroke (147) Cancer: 0.91 (0.75, 1.11)
Cancer (451)

Jacobs et al18 33 848/ Baseline FFQ/ WG bread/ Registry/ All-cause: Age, energy intake,
2001, 35–56/ WG from bread/ Women (median bread score): ICD8, ICD9/ 0.87 (0.75–1.01), sex, smoking, physical
Norway 0.80 (0.71–0.92), activity, customary
14 (1977–1994) Self-developed 0.38, 0.83, 1.13, 1.65, 2.7; All-cause (2058)
use of cod liver
Men (median bread score): CVD (758) 0.85 (0.74–0.98),
oil, customary use
0.45, 0.83, 0.90, 1.65, 3.30 Cancer (870) 0.75 (0.65–0.88); of multivitamins,
CVD: 0.93 (0.73–1.18), saturated fat, systolic
0.84 (0.68–1.05), blood pressure, serum
total cholesterol,
0.84 (0.66–1.05),
and BMI
0.77 (0.60–0.98);
Cancer: 0.96 (0.76–1.20),
0.89 (0.73–1.08),
0.90 (0.73–1.11),
0.79 (0.62–1.02)

Steffen et al 26
11 940/ Repeated FFQ / Dark bread and WG cold breakfast Family report, death All-cause: Age, race, sex, energy
2003, US 45–64/ WG food cereal (with ≥ 25% WG or bran record, registry/ 0.96 (0.79–1.17), intake, smoking,
by weight)/ N.A./ 0.80 (0.65–0.99), physical activity,
11 (1987–1999)
0.1, 0.5, 1.0, 1.5, 3.0 serving/d alcohol intake, and
All-cause (867) 0.87 (0.70–1.08),
hormone replacement
0.77 (0.61–0.97) in women

Sahyoun et al19 535/ 3-day food record/ All WG foods from 3-day food Registry/ CVD: 0.76 (0.41–1.43), Age, sex, race,
2006, US 60–98/ WG/ records/ ICD9/ 0.76 (0.41–1.41), education, marital
0.31, 0.86, 1.49, 2.9 serving/d status, smoking,
12–15 (1981– MPED CVD (89) 0.48 (0.25–0.96),
BMI, waist-to-hip
1995)
ratio, systolic blood
pressure, exercise,
energy intake,,
saturated fatty acids,
use of antihypertensive
medication, and use
of lipid-lowering
medication

Jacobs et al20 27 312 women/ Baseline FFQ/ Dark bread, cold breakfast cereal, death record/ All-cause: Age, energy intake,
2007, US 55–69/ WG food brown rice, popcorn, wheat germ, ICD9, ICD10/ 0.88 (0.81–0.96), BMI, waist-hip
bran, cooked oatmeal, other grains 0.88 (0.81–0.96), ratio, smoking,
17 (1986–2001) All-cause (5552),
(eg, bulgur, kasha, and couscous). education, physical
CVD (1900), 0.8 (0.73–0.87),
Breakfast cereals containing activity, estrogen
≥25% WG or bran./ Cancer (2099) 0.79 (0.72–0.87); use, multivitamin
0–3.5, 4–7, 7.5–10.5, 11–18.5, CVD: 0.96 (0.84–1.10), supplement use,
0.83 (0.72–0.96), and alcohol intake,
≥19 serving/wk
refined grain, coffee,
0.83 (0.71–0.96),
red meat, fish and
0.73 (0.62–0.86); seafood, and total fruit
Cancer: 0.86(0.75–0.99), and vegetables
0.95 (0.83–1.09),
0.83 (0.72–0.96),
0.89 (0.77–1.04)

(Continued )
Zong et al   Whole Grain Intake, Mortality, and CVD Mortality   2373

Table 1.  Continued


Dietary
Author questionnaire/ WG
publication year, Sample, n/ assessment/ Death confirmation/
location Age, y/ WG calculation if WG food item†/ death code/ Risk estimate compared to
Ref #, Duration, y reporting ingredients WG dose in each group Cause of death(number) reference (lowest) group Covariates
Tognon et al27 1037 Dietary history WG cereal/ Registry/ All-cause: 0.85 (0.73–1.00) Sex, BMI, waist
2011, Sweden 70/ questionnaire/ < median, >medians (74.2g in N.A./ circumference,
women and 92.8g in men) smoking, physical
NA (1971–2009) All-cause (630)
activity, marital status,
WG food
education, and birth
cohort.

Huang et al21 367 442/ Baseline FFQ/ Ready-to-eat cereals, high-fiber Registry/ All-cause: Age, gender, smoking,
2015, US 50–71/ WG/ cereals, other fiber cereals, WG ICD9, ICD10/ 0.93 (0.90–0.95), ethnicity, alcohol
bread or dinner rolls, cooked 0.89 (0.87–0.92), intake, education,
14 (1995–2009) MPED All-cause (46067),
cereal, popcorn, pancakes, marital status, health
CVD (11283), 0.85 (0.82–0.87),
waffles, French toast or crepes, status, obesity,
rice or other cooked grains, Cancer (19043) 0.83 (0.81–0.86); physical activity, red
bagels, English muffins, tortillas, CVD: 0.93 (0.88–0.98), meat, fruit and total
pasta, crackers, chips, cookies/ 0.88 (0.83–0.93), vegetables, energy
brownies, sweet pastries, and intake, and hormone
0.81 (0.77–0.86),
pies/ usage
0.83 (0.78–0.88);
0.13, 0.3, 0.47, 0.69, 1.2 serving/d
Cancer: 0.94 (0.9–0.98),
0.91 (0.87–0.95),
0.88 (0.84–0.92),
0.85 (0.81–0.89)

Roswall et al28
44 961 women/ Baseline FFQ/ WG bread, oatmeal/ Registry/ Bread Age, smoking,
2015, US 29–49/ WG food WG consumers, nonconsumers ICD9, ICD10/ All-cause: 0.83 (0.76–0.92) education, BMI,
alcohol intake, red
21 (1992–2013) All-cause (1855), Oatmeal
meat, processed meat,
CVD (270), All-cause:0.99 (0.99–1.09) and energy intake
Cancer (1,113)

Johnsen et al22 119 518/ Baseline FFQ/ Breakfast cereals, non-white Registry/ Men Age, follow-up time,
2015, 30–64/ WG/ bread, crisp bread/ N.A./ All-cause: education, smoking,
Scandinavian Men, all-cause: 0.82 (0.75–0.90), alcohol intake, BMI,
12.1 (1992– Self-developed All-cause (7839),
energy intake and
2009) 21, 37, 54, 80 g/d CHD (1156), 0.72 (0.66–0.78),
alcohol intake, with
Women, all-cause: stroke (280), 0.75 (0.68–0.82); WG products and
20, 33, 49, 74 g/d Cancer (3150) CHD: 0.79 (0.65–0.96), WG types mutually
Men, CHD: 0.8 (0.66–0.97), adjusted
21, 36, 54, 82 g/d 0.74 (0.61–0.91);
Women, CHD: Stroke: 0.7 (0.44–1.10),
21, 33, 51, 70 g/d 0.69 (0.43–1.11),
Men, stroke: 0.71 (0.44–1.15);
20, 37, 50, 79 g/d Cancer: 0.85 (0.73–0.99),
Women, stroke: 0.68 (0.58–0.79),
20, 31, 53, 76 g/d 0.74 (0.63–0.87);
Men, cancer: Women
21, 37, 54, 80 g/d All-cause: 0.8 (0.73–0.87),
Women, cancer: 0.74 (0.67–0.81),
21, 33, 49, 76 g/d 0.74 (0.67–0.81);
CHD: 0.83 (0.6–1.14),
0.59 (0.42–0.82),
0.65 (0.46–0.91);
Stroke: 0.55 (0.34–0.88),
0.5 (0.31–0.82),
0.8 (0.48–1.33)
Cancer: 0.99 (0.87–1.13),
0.94 (0.82–1.07),
0.88 (0.77–1.02)

(Continued )
2374  Circulation  June 14, 2016

Table 1.  Continued


Dietary
Author questionnaire/ WG Death confirmation/
publication year, Sample, n/ assessment/ death code/
location Age, y/ WG calculation if WG food item†/ Cause of death Risk estimate compared to
Ref #, Duration, y reporting ingredients WG dose in each group (number) reference (lowest) group Covariates
Wu et al23 74 341 women/ Repeated FFQ/ Whole wheat and whole-wheat family report or All-cause:0.98 (0.93–1.03), Age, ethnicity, BMI,
2015, US 38–63/ WG/ flour, whole oats and whole-oat registry/ 1.00 (0.95–1.05), smoking, alcohol
flour, whole cornmeal and whole- ICD8/ intake, physical
26 (1984–2010) Self-developed 0.94 (0.89–0.99),
corn flour, whole rye and whole- activity, family
All-cause (15106), 0.88 (0.84–0.93);
rye flour, whole barley, bulgur, history of diabetes
buckwheat, brown rice and brown CVD (2989), CVD: 0.97 (0.87–1.08), mellitus, cancer,
rice flour, popcorn, amaranth, and Cancer (5964) 0.96 (0.86–1.08), and heart disease,
psyllium/ multivitamin use;
0.82 (0.73–0.92),
4.2, 9.7, 14.7, 21.1, 33.0 g/d aspirin use, history
0.86 (0.76–0.96); of hypertension, high
Cancer: 1.02 (0.94–1.10), cholesterol level or
1.10 (1.02–1.19), diabetes at baseline,
energy intake,
1.06 (0.98–1.15),
postmenopausal status
0.99 (0.91–1.07) and postmenopausal
hormone use, and
alternative healthy
eating index.

Wu et al23 43 744 men/ Repeated FFQ/ Whole wheat and whole-wheat family report or All-cause: Age, ethnicity, BMI,
2015, US 32–87/ WG/ flour, whole oats and whole-oat registry/ 1.00 (0.94, 1.05), smoking, alcohol
flour, whole cornmeal and whole- ICD8/ 0.97 (0.91, 1.02), intake, physical
24 (1986–2010) Self-developed
corn flour, whole rye and whole- activity, family
All-cause (11814), 1.01 (0.95, 1.07),
rye flour, whole barley, bulgur, history of diabetes
buckwheat, brown rice and brown CVD (3621), 0.95 (0.89, 1.00); mellitus, cancer,
rice flour, popcorn, amaranth, and Cancer (3921) CVD:0.92 (0.84, 1.02), and heart disease,
psyllium/ 0.92 (0.83, 1.02), multivitamin use,
5.9, 14.4, 22.1, 31.3, 47.8 g/d aspirin use, history
0.91 (0.82, 1.01),
of hypertension, high
0.84 (0.75, 0.93); cholesterol level or
Cancer: 1.01 (0.92, 1.11), diabetes at baseline,
0.98 (0.88, 1.08), energy intake, and
alternative healthy
1.01 (0.91, 1.12),
eating index.
0.95 (0.86, 1.05)

NHANES III 11 666/ 24-hour dietary All foods containing WGs in 24- Registry/ All-cause: Age, ethnicity,
unpublished, US >20/ recall/ WG/ hour dietary recall/ ICD9, ICD10/ 0.98 (0.86, 1.12), education, physical
MPED 0, <1.5, ≥1.5 Serving/d 0.88 (0.77, 1.02); activity, smoking,
20 (1988–2010) All-cause (2545),
alcohol intake, BMI,
CVD (702), CVD: 1.11 (0.86, 1.44),
energy intake, and
Cancer (636) 0.99 (0.71, 1.39); healthy eating index
Cancer: 1.08 (0.82, 1.42),
0.84 (0.66, 1.07);

NHANES 12 488/ 24-hour dietary All foods containing WGs in 24- Registry/ All-cause: Age, ethnicity,
1999–2004 >20/ recall/ WG/ hour dietary recall ICD9, ICD10/ 0.90 (0.73, 1.11), education, physical
unpublished, US MPED 0, <1, ≥1 Serving/d 0.83 (0.65, 1.07); activity, smoking,
20 (1999–2010) All-cause (972),
alcohol intake, BMI,
CVD (229), CVD: 0.98 (0.53, 1.80),
energy intake, fruit,
Cancer (245) 0.74 (0.41, 1.32); vegetable, meat, and
Cancer: 0.72 (0.48, 1.07), added sugar
0.63 (0.37, 1.09)

BMI indicates body mass index; CI, confidence interval; CVD, cardiovascular disease; FFQ, food frequency questionnaire; HEI, Health Eating Index; ICD-8, International
Classification of Diseases, Eighth Revision; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, 10th Revision;
MPED, MyPyramid Equivalents Database; NHANES, National Health and Nutrition Examination Survey; and WG, whole grain.
*Details of whole grain calculation are provided in the online-only Data Supplement.

of individual foods (online-only Data Supplement). Study quality noninstitutionalized US residents with the primary aim of assessing
was assessed with the Newcastle-Ottawa quality assessment scale.29 the health and nutritional status of adults and children. To achieve
Scores ranged from 0 to 9 points, with higher scores indicating higher nationwide representativeness, a complex multistage probability-
study quality (Table I in the online-only Data Supplement). sampling design is used in NHANES surveys. The study protocol was
To use all available data in this meta-analysis, we also examined approved by the Institutional Review Board at the Centers for Disease
WG intake in relation to mortality in NHANES III and continu- Control and Prevention (Atlanta, GA), and written informed consent
ous NHANES surveys 1999 to 2004 and included results in the cur- was obtained from all participants. Because mortality follow-up in
rent investigation. NHANES is a series of nationwide surveys among NHANES surveys was up to the end of 2010, we included participants
Zong et al   Whole Grain Intake, Mortality, and CVD Mortality   2375

surveyed before 2005 to allow sufficient follow-up (>6 years). We Table IV in the online-only Data Supplement, WG intake
analyzed the association between WG intake and mortality in these 2 was inversely associated with total and cause-specific mor-
cohorts and included original results in this meta-analysis. WG was
estimated by linking data from a single 24-hour dietary recall to the tality, although none of the associations reached statistical
MyPyramid Equivalents Database. Mortality information was obtained significance.
by searching the National Death Index. Details of the study population Thus, 14 unique sets of results were included in the
and method are provided in the online-only Data Supplement. meta-analysis, which included 786 076 participants, 97 867
total deaths (n=12), 23 957 CVD deaths (n=11), and 37 492
Statistical Analysis cancer deaths (n=9; Table 1). Two studies reported find-
Meta-analysis was based on risk estimates from models with the most ings for WG bread and WG cereals separately,24,28 and 1
complete adjustment of potential confounders but not components of
study performed only sex-specific analysis.22 Most stud-
WGs such as cereal fiber. RRs comparing the highest and lowest WG
groups were summarized with a random-effects model.30 Statistical ies (n=10) were conducted in US populations, with the
heterogeneity was assessed with the Cochran Q test (P<0.10) and I2 remaining studies in either Scandinavian countries (n=3)
statistic.31 Analysis was stratified by study location (United States, or the United Kingdom (n=1). Median follow-up durations
Scandinavia, and other regions), WG assessments (WG ingredients,
ranged from 6 to 28 years, and study periods were between
WG foods), dietary questionnaire (single food frequency question-
naire [FFQ] at baseline, repeated FFQ during follow-up, and others), 1971 and 2010. Six studies analyzed WG foods, and 8 esti-
whether WG is the main exposure (yes, no), sample size (<20 000, mated intakes of WG ingredients (4 used the MyPyramid
≥20 000), median follow-up duration (<10 years, ≥10 years), adjust- Equivalents Database and 4 used self-developed methods).
ments for dietary factors (energy intake and other dietary confound-
Foods accounting for WG intake ranged from a single item
ing factors; yes, no), Newcastle-Ottawa Scale score (<8, ≥8), and
mean age at baseline (all adults, only >55 years). In light of the (eg, WG bread, dark bread, or WG cereals) in FFQs to a
limited number of included studies, we performed univariate meta- comprehensive list of grain-based foods available from
regressions to explore whether these factors are potential sources of 24-hour dietary recall (Table 1 and the online-only Data
heterogeneity. Publication bias was assessed by funnel plot and the
Supplement). The association between WG intake and mor-
Egger linear regression test.32
To examine the parametric relationship between WG intake and tality was the primary study aim of 10 investigations, and
mortality, we first calculated the covariance of RRs using num- the rest considered WGs a component of healthy diets or a
ber of cases and participants in each WG category and applied source of dietary fiber. Most studies applied FFQs to assess
the inverse of variance/covariance matrix as study weight in the
dietary exposure (3 used repeated FFQs, 7 used baseline
analysis.33 A 2-stage dose-response random-effects meta-analysis
was performed.34 In the first stage, a restricted cubic spline model FFQs, 2 used 24-hour dietary recall, and 1 used a diet his-
with 2 spline variables of WG intake was fitted after taking into tory questionnaire). Newcastle-Ottawa Scale scores ranged
account the correlation within each set of published RRs. In the sec- from 6 to 9, with 9 studies scoring ≥8 (Table IV in the
ond stage, the regression coefficients and the variance/covariance
online-only Data Supplement).
matrixes within each study were combined by use of the multivari-
ate extension of the method of moments in a multivariate random-
effects meta-analysis.34 We calculated the overall significance of Main Analysis
models by testing the hypothesis that the 2 regression coefficients Figure 2 shows forest plots on mortality, comparing the
equal 0, and we calculated the significance for nonlinearity by test- highest and lowest groups of WG intake. The pooled RR
ing the hypothesis that the coefficient of the second coefficient
equals 0.35 STATA commands MVMETA and GLST were used for for total mortality was 0.84 (95% CI, 0.80–0.88; P<0.001),
model fitting. All analyses were conducted with STATA version with significant heterogeneity detected among studies
12.0 (StataCorp LP, College Station, TX). (I2=74%; Pheterogeneity<0.001). For CVD mortality, 2 studies
The population-attributable fraction was calculated with the fol- provided results for coronary heart disease and stroke sep-
lowing formula: population-attributable fraction=100%×Pe(RR−1)/
(Pe[RR−1]+1), where Pe is the prevalence of WG consumption below arately, and 1 study reported only coronary heart disease
dietary recommendation among US adults, which is 92.7% accord- mortality, yielding 15 individual estimates. The pooled RR
ing to a recent analysis in NHANES 2009 to 2010.36 RR is the risk was 0.82 (95% CI, 0.79–0.85; P<0.001) without appar-
estimate from the current meta-analysis, comparing average WG con- ent heterogeneity (I2=0.0%; P heterogeneity=0.53). The RR of
sumption among US adults (0.82 serving a day) with recommended
intake (3 servings per day). cancer mortality was 0.88 (95% CI, 0.83–0.94; P<0.001),
pooling 11 individual estimates from 9 studies (I2=54%;
Results Pheterogeneity=0.02).
Of the 4062 records retrieved from initial search, 3966 were Results of stratified analysis are shown in Tables V
excluded after title and abstract screening, and 84 were through VII in the online-only Data Supplement, with sig-
excluded after full text review. We further excluded 5 mul- nificantly lower RRs observed in most subgroups. In univar-
tiple reports based on the same populations, 3 reports among iate meta-regression, heterogeneities of all-cause mortality
participants with existing CVD or cancer, 4 reports with no and cancer mortality were not explained by study location,
descriptions of WG ingredient calculation or specific WG WG assessments, dietary questionnaire, study aim, sample
food criteria, and 1 report using WG intake as a continuous size, median follow-up duration, adjustment for dietary
variable (Figure 1). Twelve studies from 11 publications were factors, Newcastle-Ottawa Scale score, or ages at baseline.
eligible for analysis. Funnel plots for publication bias are shown in Figure I in
Baseline characteristics of NHANES III (n=11 666) and the online-only Data Supplement. The Egger test did not
NHANES 1999 to 2004 (n=12 488) are provided in Tables suggest publication bias for total mortality (P=0.72), CVD
II and III in the online-only Data Supplement. As shown in mortality (P=0.21), or cancer mortality (P=0.64).
2376  Circulation  June 14, 2016

Dose-Response Analysis Studies included in this meta-analysis collectively showed


Among 10 studies that provided adequate data for dose- strong and robust inverse associations between WG intake and
response analysis, estimated median intakes across WG cat- CVD mortality. The results were in line with existing findings
egories ranged from 0.7 to 21 g/d (in a US study) to 20 to linking WG intake with CVD risk, as well as other cardio-
80 g/d (in a Scandinavian study). The dose-response relation- metabolic conditions such as type 2 diabetes mellitus. Meta-
ship between WG ingredient intake and mortality is shown in analyses of 8 to 14 prospective cohort studies reported a 21%
Figure 3. With no WG consumption used as the reference, the CVD risk reduction comparing the highest WG intake group
RRs of total mortality were 0.93 (95% CI, 0.89–0.97; P<0.001; with the lowest.8,12,13 For diabetes risk, the pooled RR com-
Figure 3A) at 10 g/d, 0.84 (95% CI, 0.77–0.91; P<0.001) at paring extreme WG groups was 0.74 (95% CI, 0.69–0.80),8
30 g/d, 0.80 (95% CI, 0.75–0.85; P<0.001) at 50 g/d, and 0.78 with each 2– to 3–servings per day increment associated with
(95% CI, 0.74–0.82; P<0.001; Ptrend<0.001; Pnonlinearity=0.06) at 21% to 32% lower risk.9,10 Two meta-analyses of clinical trial
70 g/d. For CVD mortality (Figure 3B), the RRs were 0.92 results consistently documented that WG intake lowered fast-
(95% CI, 0.88–0.96; P<0.001) at 10 g/d, 0.81 (95% CI, 0.75– ing glucose, low-density lipoprotein cholesterol, total choles-
0.89; P<0.001) at 30 g/d, 0.78 (95% CI, 0.72–0.84; P<0.001) terol, and body fat percentage.8,37
at 50 g/d, and 0.77 (95% CI, 0.68–0.87; P<0.001; Ptrend<0.001; The relationship between WG intake and cancer out-
Pnonlinearity=0.10) at 70 g/d compared with no WG consumption. comes is less clear. In our meta-analysis, significantly
For cancer mortality (Figure 3C), the RRs were 0.96 (95% lower cancer mortality was observed only when daily WG
CI, 0.91–1.01; P=0.12) at 10 g/d, 0.89 (95% CI, 0.89–0.99; consumption exceeded 30 g/d. An early meta-analysis of
P=0.04) at 30 g/d, 0.85 (95% CI, 0.76–0.94; P=0.001) at 50 40 case-control studies found that WG intakes were lower
g/d, and 0.80 (95% CI, 0.72–0.89; P<0.001; Ptrend<0.001, among patients with various types of cancer than control
Pnonlinearity=0.67) at 70 g/d compared with no WG consumption. subjects,14 although the retrospective study design of these
Because tests for nonlinear trends were not rejected (P>0.05 early studies hindered causal inference. Subsequent pro-
for all outcomes), we further estimated RRs for each 16-g/d spective studies consistently found inverse associations
increase in WG ingredient consumption (≈1 serving per day), between WG intake and colorectal cancer but not with other
which were 0.93 (95% CI, 0.92–0.94) for total mortality, 0.91 cancers.23 For example, Haas et al16 reported an inverse
(95% CI, 0.90–0.93) for CVD mortality, and 0.95 (95% CI, association between WG intake and colorectal cancer inci-
0.94–0.96) for cancer mortality. dence in a meta-analysis of 25 studies. Aune et al15 further
performed a dose-response analysis of 6 prospective stud-
Sensitivity Analysis ies and found a linear inverse association between WG food
Results of main analysis did not change in the following sensi- intake and colorectal cancer risk, with each 3-serving incre-
tivity analyses (Table VII in the online-only Data Supplement): ment associated with a 17% lower risk. It is possible that
restricting the analysis in studies eligible for dose-response the association between WG intake and cancer depends on
meta-analysis; excluding studies that used only cereals as the population characteristics and cancer types and is explained
WG source24,27,28; excluding studies that used only bread as the partly by other lifestyle and dietary factors,23 which needs to
WG source17,18,24,28; excluding the largest study by Huang et be investigated by further studies.
al21; and for CVD mortality, excluding studies that analyzed Despite limited available data, WG consumption may
only stroke mortality or coronary heart disease mortality. also contribute to lower mortality from other causes. Among
Dose-response curves were similar in the following sensitiv- >30 000 Norwegians, a nonlinear inverse association was
ity analyses: assuming that WG bread was made from 100% observed for WG bread consumption and risk of noncardio-
WG flour in studies by Steffen et al26 and Jacob et al20 (Figure vascular and noncancer deaths.18 In the Iowa Women’s Health
II in the online-only Data Supplement); assuming that 1 oz Study, intakes of WG foods were inversely associated with
equivalent of WG in MyPyramid Equivalents Database is risk of death attributed to inflammatory diseases other than
16 g dry WG ingredients (Figure III in the online-only Data CVD and cancer such as infectious diseases, respiratory sys-
Supplement); and excluding the largest study by Huang et al21 tem diseases, and digestive diseases.20 Huang et al21 found an
(Figure IV in the online-only Data Supplement). inverse association between WG intake and mortality from
respiratory diseases, infections, and other unknown causes.
Population-Attributable Fraction Johnsen et al22 also reported that WG intake was associated
Estimated population-attributable fractions were 10.4% for with lower mortality resulting from causes other than CVD,
total mortality, 11.6% for CVD mortality, and 10.2% for can- cancer, diabetes mellitus, and respiratory diseases. Clearly,
cer mortality. more data are required to further elucidate the potential ben-
efits of WGs on other health conditions.
Discussion Our analysis revealed a largely linear dose-response rela-
Our study demonstrated significant inverse associations tionship of WG intake with total and CVD mortality. Although
between WG intake and mortality from all causes, CVD, and risk estimates were less stable at very high doses because of
cancer. Further dose-response analysis showed a strong mono- limited data, the monotonically decreasing curves for WGs up
tonic association of WG with total and cause-specific mortal- to 50 g/d strongly supported the current Dietary Guidelines
ity. These findings support current dietary guidelines for WG for Americans recommendation to consume ≥3 oz equiva-
consumption that recommends ≥3 servings per day for long- lents WG foods (48 g WG ingredients) for the prevention of
term health and longevity. chronic diseases. It is critical to note that individuals should
Zong et al   Whole Grain Intake, Mortality, and CVD Mortality   2377

A All-cause mortality B CVD mortality


% %

author RR (95% CI) Weight author RR (95% CI) Weight

Key 1996(bread) 0.88 (0.79, 0.99) 6.92 Fraser 1992(CHD) 0.74 (0.56, 0.98) 2.11
Key 1996(bread,CHD) 0.85 (0.68, 1.06) 3.47
Jacobs 2001 0.75 (0.64, 0.87) 5.25
Key 1996(bread,stroke) 1.08 (0.75, 1.55) 1.32
Steffen 2003 0.77 (0.61, 0.97) 3.00
Jacobs 2001 0.77 (0.60, 0.98) 2.84
Jacobs 2007 0.79 (0.72, 0.87) 7.96
Sahyoun 2006 0.48 (0.24, 0.94) 0.38
Tognon 2011 0.85 (0.73, 0.99) 5.03
Jacobs 2007 0.73 (0.62, 0.86) 6.39
Huang 2015 0.83 (0.81, 0.86) 11.31
Huang 2015 0.83 (0.78, 0.88) 47.01
Johnsen 2015(men) 0.75 (0.68, 0.82) 8.01
Johnsen 2015(men,CHD) 0.74 (0.61, 0.90) 4.28
Johnsen 2015(women) 0.74 (0.67, 0.81) 7.94
Johnsen 2015(women,CHD) 0.65 (0.46, 0.91) 1.47
Roswall 2015(bread) 0.83 (0.75, 0.91) 7.91
Johnsen 2015(men,stroke) 0.71 (0.44, 1.15) 0.74
Roswall 2015(oatmeal) 0.99 (0.90, 1.09) 7.89
Johnsen 2015(women,stroke) 0.80 (0.48, 1.33) 0.66
Wu 2015(HPFS) 0.95 (0.90, 1.01) 10.00
Wu 2015(HPFS) 0.84 (0.75, 0.94) 14.78
Wu 2015(NHS) 0.88 (0.84, 0.93) 10.39 Wu 2015(NHS) 0.86 (0.77, 0.97) 12.53
NHANES III(unpublished) 0.88 (0.76, 1.01) 5.69 NHANES III(unpublished) 0.99 (0.71, 1.39) 1.52
NHANES 99-04(unpublished) 0.83 (0.65, 1.06) 2.69 NHANES 99-04(unpublished) 0.74 (0.41, 1.33) 0.50
Overall (I-squared = 73.7%, p = 0.000) 0.84 (0.80, 0.88) 100.00 Overall (I-squared = 0.0%, p = 0.531) 0.82 (0.79, 0.85) 100.00

NOTE: Weights are from random effects analysis NOTE: Weights are from random effects analysis

.4 .6 1 1.2 1.6 .4 .6 1 1.2 1.6

C Cancer mortality
%

author RR (95% CI) Weight

Key 1996(bread) 0.91 (0.75, 1.11) 7.03

Jacobs 2001 0.79 (0.62, 1.01) 4.92

Jacobs 2007 0.89 (0.77, 1.03) 9.88

Huang 2015 0.85 (0.81, 0.89) 20.65

Johnsen 2015(men) 0.74 (0.63, 0.87) 9.08

Johnsen 2015(women) 0.88 (0.76, 1.01) 10.65

Wu 2015(HPFS) 0.95 (0.86, 1.05) 14.60

Wu 2015(NHS) 0.99 (0.91, 1.07) 16.76

NHANES III(unpublished) 0.84 (0.66, 1.07) 5.16

NHANES 99-04(unpublished) 0.63 (0.37, 1.08) 1.25

Overall (I-squared = 53.5%, p = 0.022) 0.88 (0.83, 0.94) 100.00

NOTE: Weights are from random effects analysis

.4 .6 1 1.2 1.6

Figure 2. Meta-analysis of the association between whole grain intake and mortality from all-cause (A), cardiovascular disease (CVD; B),
and cancer mortality (C) in prospective cohort studies. Relative risks (RRs) correspond to comparisons of extreme categories of exposure
within each study. The area of each square is proportional to the inverse of the variance of the log relative risks. Horizontal lines represent
the 95% confidence intervals (CIs). Diamonds represent pooled estimates from an inverse variance–weighted random-effects model.
CHD indicates coronary heart disease; HPFS, Health Professionals Follow-up Study; NHANES, National Health and Nutrition Examination
Survey; and NHS, Nurses’ Health Study.

choose foods that are high in WG ingredients (at least 16 g Eating Index 2010 should be recommended to facilitate dis-
WG ingredients in dry weight per serving) to achieve ≈48 g/d ease prevention.43
of WG intake while maintaining a low consumption of refined Multiple bioactive compounds in WGs could contrib-
carbohydrates, which have established adverse effects.38,39 ute to the prevention of obesity, CVD, diabetes mellitus,
In this regard, low-carbohydrate diets that ignore the health cancer, poor gut health, nervous system disorders, poor
benefits of WG foods should be adopted with caution because skeletal health, and oxidative stress. The high fiber content
they have been linked to higher CVD risk and mortality.40–42 may lower cholesterol production and glucose response
Instead, diets that emphasize the quality of carbohydrates, and increase satiety, partially through inducing the pro-
fats, and proteins such as the Mediterranean diet, Dietary duction of short-chain fatty acids, which also lower car-
Approaches to Stop Hypertension diet, and Alternate Healthy cinogenic potential. The high magnesium content in WGs
2378  Circulation  June 14, 2016

A B

1.2
1.2
1.1

1.1
RR of all-cause mortality

RR of CVD mortality
1

1
.9

.9
.8
.8

.7
.7

.6
.6

.5
.5

0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Whole grain intake, g/d Whole grain intake, g/d

C
1.2
1.1
RR of cancer mortality
1
.9
.8
.7
.6
.5

0 10 20 30 40 50 60 70 80
Whole grain intake, g/d

Figure 3. Dose-response analysis for associations between whole grain intake and mortality from all-cause (A; Ptrend<0.001; Pnonlinearity=0.06),
cardiovascular disease (CVD; B; Ptrend<0.001; Pnonlinearity=0.10), and cancer (C; Ptrend<0.001; Pnonlinearity=0.67) mortality in prospective cohort
studies. The pooled linear risk trend (thick solid line) and its 95% confidence interval (thick dashed lines) were obtained by a random-
effects dose-response meta-analysis. Circles are inversely proportional to the variance of log relative risks.

may improve insulin sensitivity, suppress glucose update, cereals),4 which were included by most studies in our dose-
and lower blood pressure. WGs also contain other miner- response meta-analysis. Because of the small number of
als and constituents, including Fe, Zn, Cu, Se, polyphenols, studies available, meta-regression has limited capacity to
carotenoids, and tocopherols, thus may suppress the oxida- identify potential sources of heterogeneity. Because most
tive stress that underlies the pathogenesis of many chronic studies are from US and Scandinavian populations, it is
diseases.2 not known whether these findings can be generalized to
The strengths of our study include a large number of populations of other ethnicities. Most studies used FFQs to
participants in original studies and careful examination of collect dietary data, therefore WG intake could be under-
dose-response relationships. We standardized WG intake estimated when the list of food items was limited. Because
to reduce heterogeneity of WG estimates among individ- WG contents vary both between and within food items,
ual studies and to facilitate comparison with the Dietary measurement error in WG and misclassification of par-
Guidelines for Americans. According to sensitivity anal- ticipants are inevitable. Such random measurement errors
yses, findings were independent of differences in WG may weaken primarily the true associations in these pro-
assessment methods. Meanwhile, our study has some limi- spective studies. For studies that used short-term dietary
tations. Because included studies were carried out before assessment tools such as 3-day food records, day-to-day
a more consistent definition of WG became available,44 variations in WG intake may reduce the validity of these
lists of WG foods or food sources varied substantially assessments to reflect long-term diet. Other potential limi-
among individual studies. For US adults, >70% of daily tations include unmeasured or residual confounding from
WG intake is from breads and cereals (yeast breads/rolls, healthier lifestyles associated with high WG intake and the
quick breads, pastas/cooked cereals/rice, and ready-to-eat inclusion of participants with prevalent and unmeasured
Zong et al   Whole Grain Intake, Mortality, and CVD Mortality   2379

new onset of disease during follow-up, which may sub- 12. Tang G, Wang D, Long J, Yang F, Si L. Meta-analysis of the association
between whole grain intake and coronary heart disease risk. Am J Cardiol.
stantially change the diet at baseline or during the follow-
2015;115:625–629. doi: 10.1016/j.amjcard.2014.12.015.
up period. 13. Mellen PB, Walsh TF, Herrington DM. Whole grain intake and cardiovas-
cular disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2008;18:283–
290. doi: 10.1016/j.numecd.2006.12.008.
Conclusions 14. Jacobs DR Jr, Marquart L, Slavin J, Kushi LH. Whole-grain intake and
WG consumption was inversely associated with mortality in cancer: an expanded review and meta-analysis. Nutr Cancer. 1998;30:85–
a dose-response manner, and the association with CVD mor- 96. doi: 10.1080/01635589809514647.
15. Aune D, Chan DS, Lau R, Vieira R, Greenwood DC, Kampman E, Norat
tality was particularly strong and robust. These observations T. Dietary fibre, whole grains, and risk of colorectal cancer: systematic
endorse current dietary guidelines that recommend increas- review and dose-response meta-analysis of prospective studies. BMJ.
ing WG intake to replace refined grains to facilitate long-term 2011;343:d6617.
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Acknowledgment 10.1080/09637480802183380.
17. Fraser GE, Sabaté J, Beeson WL, Strahan TM. A possible protective effect
We are grateful to Paul Guttry for professional English editing of the
of nut consumption on risk of coronary heart disease: the Adventist Health
manuscript.
Study. Arch Intern Med. 1992;152:1416–1424.
18. Jacobs DR Jr, Meyer HE, Solvoll K. Reduced mortality among whole
Sources of Funding grain bread eaters in men and women in the Norwegian County Study. Eur
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This research was supported by National Institutes of Health grants 19. Sahyoun NR, Jacques PF, Zhang XL, Juan W, McKeown NM. Whole-
ES022981 and ES021372. Dr Sun was supported by career devel- grain intake is inversely associated with the metabolic syndrome and mor-
opment award R00-HL098459 from the National Heart, Lung, and tality in older adults. Am J Clin Nutr. 2006;83:124–131.
Blood Institute. 20. Jacobs DR Jr, Andersen LF, Blomhoff R. Whole-grain consumption is
associated with a reduced risk of noncardiovascular, noncancer death
attributed to inflammatory diseases in the Iowa Women’s Health Study.
Disclosures Am J Clin Nutr. 2007;85:1606–1614.
None. 21. Huang T, Xu M, Lee A, Cho S, Qi L. Consumption of whole grains
and cereal fiber and total and cause-specific mortality: prospective
analysis of 367,442 individuals. BMC Med. 2015;13:59. doi: 10.1186/
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CLINICAL PERSPECTIVE
Whole grains (WGs) provide various essential nutrients for long-term health and have been associated with lower risk of
many chronic diseases. However, WG consumption is largely below dietary recommendation in the United States and many
European countries. We performed the first meta-analysis of prospective cohort studies on WG intake and risk of mortal-
ity, which included 14 studies with 786 076 participants and 97 867 total deaths. Accordingly, inverse associations between
WG intake and mortality from all-cause, cardiovascular disease, and cancer were observed, and findings for cardiovascular
disease mortality were robust and strong compared with those for total and cancer mortality. All estimated WG ingredient
intakes were <80 g/d, with most studies <50 g/d. Within this range, dose-response analysis revealed a largely linear relation-
ship between the amount of WG intake and total, cardiovascular disease, and cancer mortality. Our findings corroborated
current Dietary Guidelines for Americans that recommends WG consumption of ≥3 servings per day (48 g/d WG ingredi-
ents) to facilitate the prevention of chronic diseases and premature death.