Mutagenesis vol. 26 no. 6 pp. 729–734, 2011
Advance Access Publication 6 July 2011
The Cox-2 21195 G > A polymorphism and cancer risk: a meta-analysis of
25 case–control studies
Zhipeng Tangy, Zhen-Lin Niey, Yuqin Pan, Lirong Zhang,
Lei Gao1, Qian Zhang2, Lili Qu, Bangshun He,
Guoqi Song, Ying Zhang3and Shukui Wang*
Central Laboratory of Nanjing First Hospital, Nanjing Medical University,
68 Changle Road, Nanjing 210006, China,1Luhe Hospital, Capital Medical
University, 82 Xinhua South Road, Tongzhou 101149, China,2Cancer
Hospital, Chinese Academy of Medical Sciences, Peking Union Medical
College 17 Panjiayuan South, Beijing 100021, China and3Traditional Chinese
Medicine Hospital of Kunshan, 191 Chaoyang Road, Kunshan 215300, China,
yBoth authors contributed equally to this work.
*To whom correspondence should be addressed. Central Laboratory of Nanjing
First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, China.
Tel: þ86 25 52887003; Fax: þ86 25 52887029; Email: email@example.com
Received on January 12, 2011; revised on March 15, 2011;
accepted on April 25, 2011
Cyclooxygenase 2 (Cox-2, a rate-limiting enzyme in the
conversion of arachidonic acid to prostanoids) has been
implicated in several physiological and pathological pro-
cesses, and it has been reported that polymorphisms in the
regulatory region of Cox-2 might influence its expression,
contributing to the interindividual susceptibility to cancer.
However, results from published studies on the association
between the Cox-2 21195G > A polymorphism and the
risk of cancer are conflicting. We performed a meta-
analysis based on 25 case–control studies, including a total
of 9482 cancer cases and 12 206 controls to derive a more
precise estimation of the association and its possible
influence on cancer risk. We used odds ratios (ORs) with
95% confidence intervals (CIs) to assess the strength of the
association. The overall results indicated that the variant
genotypes moderately increased risk of cancer (AA/AG
versus GG, OR 5 1.15, 95% CI: 1.02–1.31). In the
stratified analysis for the 21195G > A polymorphism,
a proximate association was observed in Asian populations
(AA/AG versus GG, OR 5 1.28, 95% CI: 1.12–1.46), but
no significant association except for oesophageal cancer
and ‘others’ was found when stratified by cancer type. In
conclusion, our meta-analysis indicates that 21195G > A
of Cox-2 is a low penetration risk factor for cancer.
Cancer is a multifactorial disease resulting from complex
interactions between environmental and genetic factors (1).
Genetic variation can modulate transcription regulation and
expression of downstream products, consequently, altering
susceptibility to cancer. It can be self-evident that genetic
variation interacting with environmental factors may play an
important role in the development of the cancer.
Cyclooxygenase 2 (Cox-2), as an inducible and immediate-
early gene, is related to several biological processes, including
inflammation, cellular proliferation, carcinogenesis and angio-
genesis (2–5). Over-expression of Cox-2 enhances the pro-
motion of angiogenesis, inhibition of apoptosis, stimulation of
invasion and suppression of immune responses. Meanwhile,
accumulating evidence indicates that selective Cox-2 inhibitors
prevent carcinogenesis in experimental animals. So far, studies
have shown that the ?1195G . A polymorphism (rs689466)
creates a c-MYB-binding site leading to higher transcriptional
activity of Cox-2 gene and Cox-2 mRNA expression compared
with the ?1195 A allele (6). The human Cox-2 gene,
mapped to chromosome 1q25.2–q25.3, is ?7.5 kb in length
and contains 10 exons (7) (Figure 1). The ?1195G . A
polymorphism is located in 10th exon, 1195 bp upstream of
the promoter region. Recently, many studies have demon-
strated association between the development of carcinoma
and ?1195G . A in various organs including lymphatic
(8,9), colorectal (10–15) and oesophagus (6,16–19). How-
ever, the cumulative results of these reports are conflicting
rather than conclusive. Considering the extensive role of
Cox-2 in the carcinogenic process, we performed a meta-
analysis on all eligible case–control studies to estimate the
overall cancer risk according to its polymorphism and to
quantify the potential influencing factors.
Materials and methods
We searched PubMed (updated to October 15, 2010) using the MeSH Terms
‘Cyclooxygenase 2’, ‘polymorphism’ and ‘cancer or carcinoma’ for relevant
reports. The search was limited to English language papers and human studies.
Additional studies were identified by hands-on searches from references of
original studies or review articles on this topic. If studies had partially
overlapping subjects, only the one with the larger and/or the latest sample size
was selected for the analysis. In our meta-analysis, the inclusion criteria for
studies were (i) evaluation of the Cox-2 ?1195G . A polymorphism and cancer
risk, (ii) being a case–control study and (iii) available useful genotype frequency.
Two investigators (Zhipeng Tang and Zhen-Lin Nie) extracted data in-
dependently and resolved any disagreements by discussion until a consensus
was reached on all the items. For each study, the following information was
collected if possible: the first author’s name, year of publication, country of
origin, ethnicity, genotype frequency in cases and controls. For studies including
subjects of different ethnic groups, data were extracted separately for each ethnic
group whenever possible. Ethnicity descents were categorized as Asian, Mixed
(i.e. including more than one ethnic group) (6,8–18,20–31) and European.
For the control group, the G allelic frequency was calculated and estimated the
heterogeneity by the v2-based Q statistic (considered significant for P , 0.05).
Odds ratios (ORs) with 95% confidence intervals (CIs) was applied to estimate
the strength of the association between the Cox-2 ?1195G . A polymorphism
and cancer risk. For all the studies, we firstly estimated the risk of the variant
genotypes AA and AG, compared with the wild-type GG homozygote and then
evaluated the risks of AA/AG versus GG and AA versus AG/GG on all cancer
types, assuming dominant and recessive effects of the variant A allele,
The Cochran’s Q-test was used to analyse the heterogeneity. If P value was
greater than 0.10, which means a lack of heterogeneity among studies, the over-
all OR estimate of each study was calculated by the fixed-effect model (the
Mantel–Haenszel method) (32). Otherwise, the random-effect model (the
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