Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects
European Journal of Epidemiology
Association between investigator-measured body-mass index and colorectal adenoma: a systematic review and meta-analysis of 168,201 subjects
Martin Chi-sang Wong 0 1 2 3
Chun-hei Chan 0 1 2 3
Wilson Cheung 0 1 2 3
Din-hei Fung 0 1 2 3
Miaoyin Liang 0 1 2 3
Jason Li-wen Huang 0 1 2 3
Yan-hong Wang 0 1 2 3
Johnny Yu Jiang 0 1 2 3
Chun-pong Yu 0 1 2 3
Harry Haoxiang Wang 0 1 2 3
Justin Che-yuen Wu 0 1 2 3
Francis Ka-leung Chan 0 1 2 3
Joseph Jao-yiu Sung 0 1 2 3
Association 0 1 2 3
0 & Joseph Jao-yiu Sung
1 State Key Laboratory of Digestive Disease, Faculty of Medicine, Chinese University of Hong Kong , Shatin , China
2 Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong , Shatin , China
3 School of Public Health, Sun Yat-sen University , Guangzhou 510080, Guangdong , China
The objective of this meta-analysis is to evaluate the odds of colorectal adenoma (CRA) in colorectal cancer screening participants with different body mass index (BMI) levels, and examine if this association was different according to gender and ethnicity. The EMBASE and MEDLINE were searched to enroll high quality observational studies that examined the association between investigator-measured BMI and colonoscopy-diagnosed CRA. Data were independently extracted by two reviewers. A random-effects meta-analysis was conducted to estimate the summary odds ratio (SOR) for the association between BMI and CRA. The Cochran's Q statistic and I2 analyses were used to assess the heterogeneity. A total of 17 studies (168,201 subjects) were included. When compared with subjects having BMI \ 25, individuals with BMI 25-30 had significantly higher risk of CRA (SOR 1.44, 95% CI 1.30-1.61; I2 = 43.0%). Subjects with BMI C 30 had similarly higher risk of CRA (SOR 1.42, 95% CI 1.24-1.63; I2 = 18.5%). The heterogeneity was mild to moderate among studies. The associations were significantly higher than estimates by previous meta-analyses. There was no publication bias detected (Egger's regression test, p = 0.584). Subgroup analysis showed that the magnitude of association was significantly higher in female than male subjects (SOR 1.43, 95% CI 1.30-1.58 vs. SOR 1.16, 95% CI 1.07-1.24; different among different ethnic groups (SOR 1.72, 1.44 and 0.88 in White, Asians and Africans, respectively) being insignificant in Africans; and no difference exists among different study designs. In summary, the risk conferred by BMI for CRA was significantly higher than that reported previously. These findings bear implications in CRA risk estimation.
Body mass index; Colorectal adenoma
Extended author information available on the last page of the article
Colorectal cancer (CRC) is a leading cause of morbidity
and mortality on a global scale [
]. Its incidence is rising
rapidly in many low- and middle-income countries [
well as Asia Pacific nations such as Japan, Korea,
Singapore and Hong Kong [
]. Overweight and obesity,
defined as a body mass index (BMI) of 25–30 and C 30 kg/
m2, respectively, is one of the recognized environmental
risk factors for the development of CRC [
obesity is preventable, statistics from the World Health
Organization reported that more than 1.9 billion adults
aged 18 years or older (39%) were overweight in 2014;
amongst them over 600 million (13%) were obese . Its
increasing prevalence has been regarded as a major
contributor to the rising trend of CRC.
Colorectal adenomas (CRA) are present in more than
30% of asymptomatic general populations [
]. Among all
CRC screening participants who received colonoscopy
with polyps detected, CRA is amongst the most frequent
pathological findings [
]. Since most CRCs develop via
genetic and morphological adenoma-carcinoma
progression from CRAs, it is widely accepted that both CRCs and
CRAs share similar epidemiological features and
etiological causes. Hence, some risk algorithms have adopted BMI
as a predictor variable to risk-stratify subjects for colorectal
Nevertheless, the association between BMI and CRA
has not been consistently demonstrated in all populations
]. Some studies reported a significant association
between BMI and CRA [
11, 12, 14–21, 23–26, 28
others did not [
13, 22, 27, 29–31
]. Two recent
meta-analyses have been performed to pool data from published
studies on the relationship between BMI and CRA. In
2012, Okabayashi and colleagues systematically reviewed
23 studies (105,190 participants) in their meta-analysis on
the prediction value of BMI for CRA, and revealed a dose–
response relationship where the risk of CRA increased with
higher BMI levels [
]. However, there exist major
limitations as self-reported BMI was used, and this could lead
to misclassification of BMI categories in public health
]. In that meta-analysis [
], a significant
proportion of studies included used self-reported
questionnaires to determine BMI and the presence of CRA, and
this could reduce the robustness of the conclusions drawn
due to possible reporting bias. In another systematic review
with the same research objective, the limitation of relying
on questionnaire surveys to measure BMI or CRA was
noticed in 15 of 36 included studies [
]. Since the
publication of these two meta-analyses, there are 10 additional
studies that were published including large number of
screening participants using physician-measured BMI and
colonoscopy diagnosed CRA as inclusion criteria. For
instance, a multi-centre study in 16 Asia Pacific countries
recruited more than 11,797 asymptomatic screening
participants who received colonoscopies, and the study was
published in 2016 [
]. The precise magnitude of the
association between BMI and CRA remains unknown, and
whether there exist differences in this association in
subjects with different characteristics is yet to be explored.
This knowledge gap is important as it bears clinical
implications in formulation of risk scores for CRA in
different patient groups, and informs clinical guidelines
regarding target groups for priority screening. This
metaanalysis aims to evaluate the odds of colorectal adenoma
(CRA) in colorectal cancer screening participants with
different body mass index (BMI) levels, and examine if this
association was different according to gender and ethnicity.
Literature search strategy
We conducted the literature search by systematically
searching MEDLINE (from 1946 to March 2017),
EMBASE (from 1974 to March 2017) and by hand
searching the reference lists of original studies and review
articles on this topic. Our search terms consisted of three
main components, colorectal (colorectal OR colon OR
colonic OR rectum OR rectal) AND disease (cancer* OR
neoplas* OR tumor* OR tumour* OR carcinoma* OR
sarcoma* OR adenoma* OR lesion* OR polyp* OR CRC)
AND obesity or overweight (body mass index OR BMI OR
body size OR body weight OR intraabdominal OR
overweight OR fat OR obesity OR obese OR waist) [
(Supplementary File 1). Grey literature search was
performed in Grey Literature Report (www.greylit.org),
related thesis, and conference reports. No language restrictions
Inclusion and exclusion criteria
CRA, defined as the presence of either non-advanced or
advanced adenoma, is the primary outcome of this study.
We included all cross-sectional studies, case control studies
and cohort studies that examined the relationship between
BMI and the prevalence of CRA. In these studies, odds
ratios (OR) with 95% confidence intervals (CI) between
CRA and BMI categories were recorded. We excluded the
following studies: (1). those with hyperplastic polyps,
serrated adenomas or CRC cases as majority of all lesions;
(2). those where subjects had higher CRC risk as compared
to the general population, for instance, individuals with a
family history of CRC in first-degree relatives; (3). those
that could not generate OR for BMI category and CRAs;
(4). those with symptomatic participants; (5). those with
BMI data obtained from self-reported questionnaires; (6).
those with CRA not diagnosed by colonoscopy and
histological examination; (7). those with CRA data not derived
from the whole colon and rectum. The eligibility of studies
was assessed by two investigators (J. L. H. and C. H. C.)
and in cases of disagreement, consensus was made via
referral to a third reviewer (M. C. S. W.). We attempted to
contact authors of studies if there were any missing data.
Quality assessment of selected studies
The Newcastle Ottawa Scale (NOS) was employed to
evaluate the quality of the included studies according to
their design by two assessors (J. L. H. and C. H. C.) who
are librarian experts [
]. The NOS was used to
confirm that the included studies are of high quality, which
was scored based on the summation of items described
below. Similar items among different study types for
quality assessment were as follows: (1) representativeness
of the samples: one point was assigned if the subjects
represent the general population/case group/controls
group/exposed cohort/non-exposed cohort. No points were
assigned if samples are special population groups (e.g.
veteran) or not mentioned; (2) ascertainment of the
exposure: one point was assigned if measurement of BMI was
performed by healthcare professionals, 0 point was
assigned if BMI was self-reported or not specified. Since
all our included studies measured BMI by healthcare
professionals, none was assigned 0 point; (3) comparability:
for subjects in different outcome groups or case/control
groups, two points were assigned for adequate adjustment
of recognized risk factors for colorectal adenoma; one
point for adjustment of some covariates only, and zero
point for no adjustment; (4) assessment of the outcome:
colonoscopy and histological examination: one point was
assigned if it was based on medical records or histology
report, no point was given if the assessment was
self-reported by study participants or not specified.
For cross-sectional studies, additional items for quality
assessment include: (1) sample size: if the sample size is
justified, one point was assigned, otherwise no point was
given; (2) non-respondents: one point was assigned if the
response rate is satisfactory, otherwise no point; (3)
assessment of the outcome: for those studies in which
outcome assessment was independent and blinded, one
extra point was added accordingly; (4) statistical test: one
point was assigned if the statistical test is appropriate,
clearly described and complete; otherwise no point was
assigned. For case-control studies, additional items
include: (1) same method of ascertainment for cases and
controls: one point was assigned; (2) non-response rate:
one point was given if the rate for both case and control
groups was the same, and no point was assigned for
nonrespondents. For cohort studies, the additional items are:
(1) demonstration that outcome of interest was not present
at study commencement: one point was assigned for stating
exclusion of CRA/ advanced CRA/ CRC subjects or stating
subjects have no history of CRA/ advanced CRA/ CRC; (2)
follow-up duration: one point was assigned for all eligible
studies if the follow-up period is long enough to detect
CRA; (3) adequacy of following up of cohorts: one point
was assigned for completing at least 90% of follow-up.
Scores ranged from 0 (lowest) to 9 (highest). Similar to
previous literature [
], studies with scores C 7 were
classified as ‘‘high’’ quality and those with scores \ 7 were
classified as ‘‘low’’ quality.
The characteristics of studies were recorded, including the
names of the first authors, publication year, country,
design, enrolment year, BMI category, strategies to capture
BMI data, the definition of non-cases and the definition of
advanced adenoma. BMI is categorized according to WHO
classification: normal (\ 25 kg/m2), overweight
(25–30 kg/m2) and obese (C 30 kg/m2). The number of
cases and non-cases in the 3 categories, as well as the study
design, gender and subject ethnicity, were recorded if
available. Data extraction and data checking were
performed by 3 investigators (J. L. H., C. H. C. and W. C.)
Random effects model meta-analysis was conducted to
synthesize a summary estimate of the association between
different BMI groups and CRA. Summary odds ratios
(SOR) with 95% confidence intervals (CI) were used as a
proxy measure for effect size, and were calculated by
comparing 3 BMI categories (C 25, 25–30, C 30 kg/m2)
with BMI \ 25 kg/m2. The SOR was computed with the
assumption that the outcomes categorized by different BMI
groups were derived from patients independently, so there
was no within-study correlation of adenoma prevalence.
Z-tests were used to investigate the significance of pooled
estimate, and Cochran’s Q and I2 statistics were used to
examine the heterogeneity within groups and between
]. For publication bias, funnel plot asymmetry
was assessed by the Egger’s and Begg’s regression test
]. Subgroup analysis was applied in this study to
perform comparisons according to subsets of studies, such
as study design, gender, ethnicity, types of adenoma and
degree of CRA progression. We also conducted a
metaregression analysis to explore heterogeneity between the
In the present study, R ver. 3.3.1 (The R Foundation for
Statistical Computing) with metafor package ver. 1.9–9
was used to conduct the statistical analysis [
functions were performed under restricted maximum
likelihood estimation. Two-tailed p value \ 0.05 was defined
as statistical significant for all the comparisons.
Heterogeneity was considered as low, moderate and high, when I2
was 25, 50 and 75% respectively. This systematic review
was written following the PRISMA guideline [
Search results and study characteristics
The search strategy yielded 3292 citations. We removed
1027 duplicates, and 2173 articles were removed after title
and abstract review (Fig. 1). A total of 92 studies were
reviewed in full text and 13 studies fulfilled our eligibility
criteria. Four additional articles were retrieved from review
of the reference sections of original articles and grey
literature search, resulting in 17 articles included for data
analysis (168,201 subjects). Among them, 12 were
crosssectional studies [
24, 34, 43–52
], 4 were case-control
], and one was a cohort study [
] (Tables 1,
2). The quality of all included studies was assessed by the
Newcastle Ottawa Scale (NOS) (Table 3). All studies were
found to have good quality, with 15 studies scoring 8 points
and 2 studies scoring 7 points. Of all the 17 studies, 11
included data of Asian subjects [
24, 44–51, 53, 56
included data of white subjects and 4 included data of
individuals of African descent [
46, 52, 55, 56
proportion of screening participants with BMI [ 25 kg/m2
Fig. 1 Flow diagram of study
was 29.3, 49.7 and 58.1% in Asian, African and white
subjects, respectively. No studies were found to use
identical cohorts. The search did not identify any studies
published in grey literature.
The association between body mass index and colorectal adenoma
Meta-analysis of the included articles via a random-effects
model showed a SOR of 1.42 (95% CI 1.34, 1.51) among
subjects with BMI C 25 compared to subjects with BMI
\ 25, where the heterogeneity was moderate and
statistically insignificant (I2 = 34.3%, pheterogeneity = 0.063)
(Fig. 2a). Using BMI \ 25 as a reference, the associations
with any CRA were similar between those with BMI 25–30
(SOR 1.44, 95% CI 1.30, 1.61; I2 = 43.0%,
pheterogeneity = 0.099; Fig. 2b) and BMI C 30 (SOR 1.42, 95% CI
1.24, 1.63; I2 = 18.5%, pheterogeneity = 0.193; Fig. 2c). No
statistically significant difference were found between the
two groups [p difference = 0.887]. All 17 studies reported
data on CRA among subjects with BMI [ 25, but only 10
studies reported number of CRA among subjects with BMI
Polyp-free (n, %)
HP (n, %)
Non-AA (n, %)
AA (n, %) CRC (n, %)
Definition of normal Definition of AN
Normal definition: 1: non-adenomatous; 2: polyps-free; 3: normal findings
HP hyperplastic polyp, AN advanced neoplasia, CRA colorectal adenoma, CRC colorectal cancer, AA advanced adenoma, adenoma measuring
[ 10 mm in diameter and/or with villous components and/or showing high grade dysplasia (32)
#Mixed with polys-free and HP (hyperplastic polyp)
*Mixed with any adenomas
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25–30 and BMI [ 30 kg2/m. The magnitude of association
was similar between different BMI groups and
non-advanced adenoma (BMI C 25 vs. \ 25: SOR 1.36, 95% CI
1.26, 1.47; BMI 25–30 vs. \ 25: SOR 1.33, 95% CI 1.22,
1.47; BMI C 30 vs. \ 25: SOR 1.38, 95% CI 1.04, 1.84)
and did not show statistically significant difference when
compared with any CRA. When compared with subjects
with BMI \ 25, the odds of advanced adenoma was
significantly higher among those with BMI C 25 (SOR 1.52,
95% CI 1.32, 1.73). The relationship between BMI and
advanced adenoma using ‘‘non-advanced adenoma’’ as
non-cases did not show statistical significance.
Eight studies examined the association in men and women
separately, and it was found that female subjects had
significantly higher odds of CRA (SOR 1.43, 95% CI 1.30,
1.58) when compared with men (SOR 1.16, 95% CI 1.07,
1.24; between-groups p difference of \ 0.001) (Fig. 3).
Among subjects of white ethnicity (SOR 1.72, 95% CI
1.44, 2.07) and Asian ethnicity (SOR 1.44, 95% CI 1.32,
1.57), individuals with BMI [ 25 kg/m2 had higher odds
of CRA than those with BMI \ 25 kg/m2. The odds was
higher compared to Africans but the findings indicated only
a significant difference between Asian and Africans. The
SORs between BMI and CRA showed no statistically
significant difference between cross-sectional and case control
studies (p = 0.479). Meta-regression analysis based on
BMI 25–30 as a reference and BMI[30 kg/m2 implied that
different levels of BMI could not explain the heterogeneity
observed in this meta-analysis (coefficient - 0.01 [95% CI
- 0.20, 0.18], p = 0.905).
The Egger’s test (t = - 0.560, p = 0.584) and Begg’s test
(Kendall’s tau = 0.059, p = 0.777) for funnel plot
asymmetry identified insignificant publication bias (Fig. 4).
There were two outliers in the funnel plot, and the trim and
fill analysis showed no missing studies. When these two
] were excluded and the association between
any CRA and BMI (C 25 vs. \ 25) was re-examined, the
SOR was 1.41 (95% CI 1.34, 1.49) which was statistically
similar to the SOR computed from all studies.
This systematic review and meta-analysis based on high
quality studies reported increased risks of any CRA and
non-advanced adenomas in the overweight and obese
populations by a magnitude of 33–44%—risk estimates
that are significantly higher than those reported previously.
BMI was found to be a significant factor associated with
detection of CRA in terms of its magnitude, and hence
should be considered as an important factor in risk
algorithms predicting the risk of CRA. The strength of
association between BMI and CRA was higher in female
subjects and individuals of western or Asian ethnicities, but
was insignificant in subjects of African descent.
This meta-analysis is distinct from previous systematic
reviews by restricting analysis to the most updated studies
retrieved from a broad search strategy that included the
most comprehensive data. This enables more robust
evaluations on the association between BMI and CRA,
allowing a more precise magnitude to be determined.
Several limitations should, nevertheless, be addressed.
Firstly, the assessment of BMI and CRA might not be
universally standardized among different studies, and it is
well recognized that there is a higher likelihood for obese
patients, or subjects with different characteristics, to
present with poorer bowel preparation at colonoscopy
]. Therefore, the summary odds ratios
identified in the present study might have been
underestimated. Second, the calendar years where CRA were
detected are different across studies, where
colonoscopists with different levels of experience and expertise
were involved. The adenoma detection rate might
increase with time due to higher prevalence with rapid
urbanization and more affluent lifestyles. Also, there have
been very few prospective cohort studies that followed-up
screening subjects and examine the direct influence of
obesity on CRA development . Furthermore, the
estimation of dose-response association requires at least
three non-reference dose levels [
]. As most original
studies included in this meta-analysis only used two
nonreference dose levels (BMI 25–30, BMI [ 30, reference:
BMI \ 25), dose-response meta-analysis could not be
performed. From one cohort study (Sedjo et al. [
association between CRA and obesity vs. overweight
(adjusted OR 2.16, 95% CI 1.13–4.14 vs. OR 1.54, 95%
CI 0.81–2.91) suggested a trend towards dose-response
relationship, although statistical analysis did not confirm
such relationship. The cross-sectional nature of most
studies included in this meta-analysis might obscure a
potential dose-response association. In addition,
multivariate meta-regression analysis could not be performed
since we need an appropriately large ratio of studies to
]. In this meta-analysis it is not feasible due
to multiple covariates and the small number of studies.
Lastly, as the majority of studies included in this
metaanalysis are cross-sectional or case-control studies, one
could not infer a cause-and-effect relationship between
BMI and CRA.
The exact mechanisms of colorectal carcinogenesis
induced by obesity are still not entirely clear. Our study
findings reported a significant association between BMI
and CRA, but when the outcome measure is development
of non-advanced CRA to advanced CRA, the association
becomes insignificant. This implies that obesity could
exert, to a larger extent, its influence on risk of adenoma,
but less so on adenoma progression. There has been a
postulation that genetic alteration like the common
single-nucleotide polymorphism variants around the
melanocortin 4 receptor gene could be associated with the
cooccurrence of obesity and CRA [
]. Alternatively, it
has been hypothesized that insulin resistance and
subsequent hyperinsulinemia induced by obesity may lead
to direct mitogenic and antiapoptotic signaling by insulin
or insulin-like growth factor axis [
obesity has been regarded as a condition of chronic
lowgrade inflammation with elevation of pro-inflammatory
cytokines, including tumor necrosis factor and
interleukin-6. These inflammatory mediators have direct
tumorigenic effects on the gastrointestinal tract [
From a recent meta-analysis, leptin and adiponectin have
also been implicated in the pathogenesis of CRA in
obese patients . In addition, there are metabolic,
lipidomic and transcriptomic differences between
visceral adipose tissue (VAT) and subcutaneous adipose
tissue (SAT) compartments in colorectal carcinogenesis
], which have not been differentiated in this study.
There is emerging evidence demonstrating that the
relationship between obesity and cancer is mediated by
VAT rather than SAT. Several studies have identified a
unique role of VAT in the risk and progression of CRC.
It has been postulated that VAT alters metabolic activity
and induces chronic systemic inflammation that
promotes a pro-oncogenic environment [
]. Future studies
may explore the magnitude of association between VAT
We found that a 5-unit increase of BMI conferred an up
to 44% increased risk for CRA. This additional risk is
significantly higher than that estimated by previous
]. The increased risk estimated by
Okabayashi et al and Ben et al in 2012 was 24 and 19%,
respectively. The difference could be explained by
different inclusion criteria of original studies in these
metaanalyses. In their evaluations, studies that included
selfreported BMI and questionnaire-measured CRA were also
included in their systematic review. Studies showed that
BMI based on self-reports were more frequently
underreported, where data from measurement devices usually
revealed higher proportions of overweight and obesity
]. Hence, the true association between BMI and
CRA might be biased towards lower risk. In addition,
except on cohort study, this meta-analysis mainly included
case-control and cross-sectional studies. Risk estimates are
therefore higher in retrospective studies as compared to
previous meta-analyses, which also included prospective
Our study also found that the association between BMI
and CRA was significantly higher in women than men, in
the context of higher prevalence of CRC in men when
compared with women. It has been suggested that this
gender difference might be due to the role of endogenous
and exogenous sex hormones on the adenocarcinoma
]. It is well recognized that pre-menopausal
women had a stronger susceptibility to CRA development
due to endogenous estrogen secretion, where activation of
estrogen receptor-a leads to increase in gene transcription
and cancer proliferation [
]. As for the differences in the
association between BMI and CRA, ethnicity of
individuals was found to be a significant effect modifier. In
particular, the association between BMI and CRA was found
to be absent in subjects of African descent. The difference
in prevalence of overweight and obesity in individuals
according to ethnicity might affect the comparability
among studies that included screening participants of
different ethnic groups. From existing literature, the
magnitude of this association has not been adequately examined,
and the exact reasons of this observation will need to be
explored in future studies.
These study findings showed that being overweight
(BMI 25–30) is associated with similar risk for CRA when
compared with obesity (BMI C 30), and hence bring forth
an alert to physicians and public health practitioners on
early intervention for overweight patients in order to
reduce future risk of CRA. In addition, our data showed
that risk algorithms for CRA would need to take gender
and ethnicities into account for more accurate risk
prediction, and these findings could be used for devising such
risk-stratification scores. Future studies should examine the
mechanistic aspects of the differential effects of these
variables on CRA development. As there is a scarcity of
prospective studies on the impact of BMI on progression of
CRA to advanced CRA, additional longitudinal cohort
evaluations should be performed with strategies that
address confounding and selection biases.
Compliance with ethical standards
Conflict of interest None declared from all authors.
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Institute of Digestive Disease, Faculty of Medicine, Chinese
University of Hong Kong, Shatin, China
School of Public Health and Primary Care, Faculty of
Medicine, Chinese University of Hong Kong, Shatin, China
School of Basic Medicine, Peking Union Medical College
and Institute of Basic Medical Sciences, Chinese Academy of
Medical Sciences, Beijing 100050, China
Peking Union School of Public Health, Chinese Academy of
Medical Sciences and Peking Union Medical College,
Beijing 100050, China
Li Ping Medical Library, Chinese University of Hong Kong,
Shatin, HKSAR, China
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