Mol Biol Rep DOI 10.1007/s11033-014-3290-7
GSTP1 Ile105Val polymorphism is associated with lung cancer risk among Asian population and smokers: An updated meta-analysis Chun-hua Xu • Qin Wang • Ping Zhan Qian Qian • Li-Ke Yu
•
Received: 18 March 2013 / Accepted: 13 February 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Many studies have examined the association between the GSTP1 Ile105Val (rs 1695) gene polymorphism and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed and CNKI database was searched for case–control studies published up to July 2012. Data were extracted and pooled odds ratios (OR) with 95 % confidence intervals (CI) were calculated. Ultimately, 42 studies, comprising 12,304 lung cancer cases and 15,729 controls were included. Overall, for G allele carriers (GA ? GG) versus homozygote AA, the pooled OR was 1.05 (95 % CI 0.99–1.10 P = 0.092 for heterogeneity), for GG versus AA the pooled OR was 1.04 (95 % CI 0.96–1.12 P = 0.084 for heterogeneity). In the stratified analysis by ethnicity, gender, histological types of lung cancer and smoking status, a significant association was found in Asians and smokers, not in Caucasian or mixed population, Male, Female population, lung AC, SCC, SCLC or nonsmokers. Publication bias was found by using the funnel plot and Egger’s test. Overall, there is no evidence showing a significant correlation between GSTP1 Ile105Val gene polymorphism and lung cancer risk in overall population, however stratified analysis by ethnicity, histology, gender
C–H. Xu and Q. Wang contributed equally to this work and should be considered as co-first authors. C. Xu P. Zhan Q. Qian L.-K. Yu (&) First Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing 210029, China e-mail: [email protected] Q. Wang Department of Critical Care Medicine, 81 Hospital of PLA, Nanjing, China
and smoking status, it correlate with increased lung cancer susceptibility among Asians and smokers. Keywords GSTP1 Polymorphism Lung cancer Susceptibility Meta-analysis
Introduction Lung cancer remains the most lethal cancer worldwide, despite improvements in diagnostic and therapeutic techniques [1]. Its incidence has not peaked in many parts of world, particularly in China, which has become a major public health challenge all the world [2]. The mechanism of lung carcinogenesis is not understood. Although smoking status is the single most important factor that causes lung cancer, host factors including genetic polymorphism, had garnered interest with regard to the study of the tumorigenesis of lung cancer [3]. Otherwise, accumulating studies have suggested that lung cancers occurring in never smokers have different molecular profiles. In this way, host genetic susceptibility is a very important factor in the development of lung cancer, contributing to the variation in individual cancer risk. The glutathione S-transferases (GST) are a family of phase II enzymes that, by means of conjugation with glutathione, metabolize carcinogenic compounds that are found in tobacco smoke, combustion products, and diet [4]. These enzymes are encoded by different gene loci that are known to present polymorphisms that may compromise protein functionality. Cytosolic GST enzymes occupy a key position in biological detoxification processes [5]. They are classified according to their genetic and biochemical properties like alpha (GSTA), mu (GSTM), theta (GSTT), pi (GSTP), and omega (GSTO) [6].
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Mol Biol Rep Fig. 1 The flow diagram of search strategy
GSTP1 (rs 1695), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity [6]. Therefore, individuals with reduced or loss of GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Thus, associations between genetic polymorphism and development of environmental cancer clearly indicate the increased need to elucidate the effects of various polymorphic genes on cancer susceptibility and adverse health outcomes [7]. The predominant homozygous genotypes, the heterozygous genotypes and the homozygous rare genotypes of the GSTP1 Ile105Val gene polymorphism are named the homozygous wild-type genotype (A/A), the heterozygote (A/G) and the homozygote (G/G), respectively. Recently, many studies have investigated the role of the GSTP1 Ile105Val gene polymorphism in lung cancer. However, the results of these studies remain inconclusive. A single study might not be powered sufficiently to detect a small effect of the polymorphisms on lung cancer, particularly in relatively small sample sizes. Further, some studies have not controlled for the potential confounding effect of smoking properly-the main risk determinant for lung cancer. Various types of study populations and study designs might also have contributed to these disparate findings. To clarify the effect of the GSTP1 Ile105Val gene polymorphism on the risk for lung cancer, we performed a meta-analysis of all eligible case–control studies that have
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been published and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung caner, gender and smoking status of case and control population.
Materials and methods Publication search We searched for studies in the PubMed and CNKI (China National Knowledge Infrastructure) electronic databases to include in this meta-analysis, using the terms ‘‘GSTP1,’’ ‘‘glutathione S-transferase pi,’’ ‘‘polymorphism,’’ and ‘‘lung cancer.’’ An upper date limit of July 01, 2012 was applied; no lower date limit was used. The search was performed without any restrictions on language and was focused on studies that had been conducted in humans. We also reviewed the Cochrane Library for relevant articles. Concurrently, the reference lists of reviews and retrieved articles were searched manually. Only full-text articles were included. When the same patient population appeared in several publications, only the most recent or complete study was included in this meta-analysis. Inclusion criteria For inclusion, the studies must have met the following criteria: they (1) evaluated GSTP1 gene polymorphisms and lung cancer risk; (2) were case–control studies or nestedcase control study; (3) supplied the number of individual genotypes for the GSTP1 Ile105Val gene polymorphisms in
Mol Biol Rep Table 1 Distribution of GSTP1 Ile105Val genotypes among lung cancer cases and controls included in this meta-analysis First author-year
Ethnicity (country of origin)
Mean age of cases
Male/female ratio
Total sample size (case/control)
Lung cancer cases
Controls
A/A
A/G
G/G
A/A
A/G
G/G
Dzian A-2012
Caucasian (Slovak)
62.5
2.93
230/290
115
91
24
153
115
22
Ada AO-2011
Caucasian (Turkey)
56
9.65
213/231
133
80#
133
98#
Ihsan R-2011
Asian (India)
60.4
3.37
188/290
102
77
179
96
9 #
Gervasini G-2010
Caucasian (Spain)
66
N/A
115/302
53
50
Timofeeva M-2010
Caucasian (Germany)
45.1
1.75
638/1,300
279
260
Lam TK-2010
Mixed (USA)
66.3
3.99
474/382
236
238#
Yadav DS-2010 Cote ML-2009
Asian (India) Mixed (USA)
N/A 59.7
N/A N/A
101/221 504/527
54 112
47 251
Kumar M-2009
Asian (India)
39.8
4.06
93/2,253
48
Yue Z-2009
Asian (China)
N/A
N/A
102/102
64
Honma HN-2008
Caucasian (Brazil)
N/A
2.57
200/264
82
93
Sobti RC-2008
Asian (India)
56.9
6.19
151/151
78
68
Sreeja L-2008
Asian (India)
57.8
6.91
111/111
116
74
Yoon KA-2008
Asian (Korea)
57
N/A
213/213
165
45
3
Reszka E-2007
Caucasian (Poland)
N/A
N/A
404/410
108
106#
104 69
15 #
143
540
591
172
210#
136
134
132 128
89 244
39
6
150
94
36
2
64
35
3
25
105
129
30
5
62
83
6
21
134
67
10
179
31
3
120
131#
151 9
Yang M-2007
Asian (Korea)
55.4
2.08
671/318
198
103
16
248
93
12
Sorensen M-2007
Caucasian (Denmark)
N/A
1.23
430/767
194
180
55
349
323
94
Zhang T-2006
Asian (China)
N/A
N/A
121/121
59
46
16
81
33
7
Larsen JE-2006
Caucasian (Australia)
63.4
0.56
1103/627
501
484
110
273
269
84
Miller DP-2006
Caucasian (USA)
N/A
0.92
1,921/1,343
885
816
220
579
623
141
Cao YF-2005
Asian (China)
N/A
N/A
97/197
66
26
5
143
46
8
Wenzlaff AS-2005 Wenzlaff AS-2005
Caucasian (USA) Mixed (USA)
62.4 62.4
0.73 0.73
135/151 166/181
39 47
58 73
15 21
61 68
72 90
18 22
Liang G-2005
Asian (China)
N/A
2.84
227/227
135
83
9
132
86
9
Chan EC-2005
Asian (China)
N/A
4.76
75/162
45
28
2
112
46
4
Cote ML-2005
Caucasian (USA)
42.4
1.12
247/290
79
127
22
109
141
38 19
Cote ML-2005
Mixed (USA)
41.4
0.74
103/120
16
60
13
37
63
Liang GY-2004
Asian (China)
N/A
N/A
152/152
94
54
4
105
43
4
Yang P-2004
Mixed (USA)
N/A
N/A
237/234
94
110
31
104
90
39
Schneider J-2004
Caucasian (Germany)
64.4
9.61
446/622
198
186
62
298
254
70
Lin P-2003
Asian (China)
N/A
2.6
198/332
124
74#
226
106#
Reszka E-2003
Caucasian (Poland)
59.7
2.86
138/165
73
60
5
83
77
Wang J-2003
Asian (Japan)
56.5
1.8
112/119
67
44
1
84
34
1
Wang Y-2003
Caucasian (USA)
60.9
1.10
362/419
149
178
35
182
193
44
Nie L-2002
Asian (China)
N/A
N/A
158/168
89
59
10
98
58
12
Lewis SJ-2002
Caucasian (UK)
58
1.8
93/151
34
53
6
64
74
13
Perera FP-2002 Stu¨cker I-2002
Mixed (USA)
N/A
N/A
89/173
33
52#
77
81#
Katoh T-1999
Caucasian (France) Asian (Japan)
59.5 64.6
N/A N/A
251/264 47/122
120 34
101 13
30 0
124 93
120 24
20 5
Kihara M-1999
Asian (Japan)
62
N/A
358/257
278
86
18
184
65
8
To-Figueras J-1999
Caucasian (Spain)
N/A
N/A
164/332
83
64
17
154
144
34
Harris MJ-1998
Mixed
66
N/A
178/199
79
73
26
80
101
18
Jourenkova-MN-1998
Caucasian (France)
N/A
N/A
150/172
67
66
17
86
64
22
Ryberg D-1997
Caucasian (Norway)
62.3
N/A
138/297
53
63
22
153
117
27
#
5
The number of the combined A/G and G/G genotypes
N/A not applicable
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lung cancer cases and controls, respectively; and (4) demonstrated that the distribution of genotypes among controls were in Hardy–Weinberg equilibrium. Data extraction Information was extracted carefully from all eligible publications independently by two authors, based on the inclusion criteria above. Disagreements were resolved through a discussion between the two authors. The following data were collected from each study: first author’s surname, year of publication, ethnicity, total numbers of cases and controls, and numbers of cases and controls who harbored the GSTP1 Ile105Val genotypes, respectively. We did not contact the author of the primary study to request the information. Ethnicities were categorized as Asian, Caucasian, and mixed population. Histological type of lung cancer was divided to lung squamous carcinoma (SCC), adenocarcinoma (AC) and small cell lung cancer (SCLC) in our meta-analysis. The definition of smoking history is very complicated. The smoking histories covered different periods if changes in the number of cigarettes smoked per day or type of tobacco products occurred. According to the general standards, non-smokers were defined as subjects who had smoked less than 100 cigarettes in their lifetime. Although the precise definition of never-smoking status varied slightly among the studies, the smoking status was classified as non-smokers (or never smoker) and smokers (regardless of the extent of smoking) in our meta-analysis. We did not require a minimum number of patients for a study to be included in our metaanalysis. The data extraction and quality assessment were reported in previous meta-analysis [8–15]. Statistical analysis OR (odds ratios) with 95 % CIs were used to determine the strength of association between the GSTP1 Ile105Val polymorphisms and lung cancer risk. The pooled ORs for the risk associated with the GSTP1 Ile105Val genotype, the G allele carriers (GA ? GG) versus the wild-type homozygotes (AA), GG versus AA were calculated, respectively. Subgroup analyses were done by ethnicity, gender, histological types of lung cancer and smoking status. Heterogeneity assumptions were assessed by Chi square-based Q test [16]. A P value greater than 0.10 for the Q test indicated a lack of heterogeneity among the studies. If P value of Q test for heterogeneity test was greater than 0.10, the pooled OR estimate was performed using the fixed-effects model (the Mantel–Haenszel method) according to the calculation principle of STATA software [17]; otherwise, the random-effects model (the DerSimonian and Laird method) was used
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[18].One-way sensitivity analyses were performed to determine the stability of the results-each individual study in the meta-analysis was omitted to reflect the influence of the individual dataset on the pooled OR [19]. Potential publication biases were estimated by funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetrical plot suggests a publication bias. Funnel plot asymmetry was assessed by Egger’s linear regression test, a linear regression approach that measures the funnel plot asymmetry on a natural logarithm scale of the OR. The significance of the intercept was determined by t test, as suggested by Egger (P \ 0.05 was considered a statistically significant publication bias) [20]. All calculations were performed using STATA, version 11.0 (Stata Corporation, College Station, TX).
Results Study characteristics One hundred and eighty-nine potentially relevant citations were reviewed, and 42 publications [21–62] met the inclusion criteria and included in our meta-analysis (Fig. 1). Table 1 presents the principal characteristics of these studies. Cote ML and Wenzlaff AS’s study [42, 45] sorted the data for Caucasians and Asians; therefore, each group in the study was considered separately in the pooled subgroup analyses. Of the 42 publications, 36 were published in English and 6 were written in Chinese. The sample sizes ranged from 169 to 3,264. All cases were histologically confirmed. The controls were primarily healthy populations and matched for age, ethnicity, and smoking status, 15 studies were hospital-based control and 27 were population-based control. There were 18 groups of Asians, 19 groups of Caucasians, and 7 mixed populations. All polymorphisms in the control subjects were in Hardy–Weinberg equilibrium. Meta-analysis results Table 2 listed the main results of this meta-analysis. Overall, for the G allele carriers (GA ? GG) versus homozygote AA, the pooled OR for all studies combined 12,304 cases and 15,729 controls was 1.05 (95 % CI 0.99–1.10 P = 0.009 for heterogeneity) (Fig. 2), for GG versus AA the pooled OR was 1.04 (95 % CI 0.96–1.12 P = 0.084 for heterogeneity). For all studies in the meta-analysis, no significant risks were found for the G allele carriers (GA ? GG) versus homozygote AA or GG versus AA, and heterogeneity was not found in all studies.
Mol Biol Rep
In the stratified analysis by ethnicity, significant risks were found among Asians for (GA ? GG) versus AA (OR = 1.24, 95 % CI 1.12–1.37 P = 0.233 for heterogeneity) or GG versus AA (OR = 1.22; 95 % CI 1.16–1.59 P = 0.016 for heterogeneity). For Caucasians, significant risks were not found for (GA ? GG) versus AA (OR = 0.97, 95 % CI 0.91–1.04 P = 0.260 for heterogeneity) or GG versus AA (OR = 0.94; 95 % CI 0.87–1.03 P = 0.090 for heterogeneity). Sixteen out of 42 studies examined the association of the GSTP1 Ile105Val genotype and the risk of different histological types of lung cancer including SCC, AC and SCLC (Table 3). Among lung SCC, lung AC or SCLC, no significant increased risks were observed for both (GA ? GG) versus AA or GG versus AA (Fig. 3). Eleven out of 42 studies included the association of GSTP1 Ile105Val genotypes and lung caner risk stratified by smoking status (non-smokers or never smokers and smokers) (Table 4). For smokers, significantly increased risks were observed for (GA ? GG) versus AA (OR = 1.13, 95 % CI 1.01–1.26 P = 0.582 for heterogeneity) or GG versus AA (OR = 1.18; 95 % CI 1.08–1.35 P = 0.360 for heterogeneity). However, for non-smokers, no significant associations were observed for (GA ? GG) versus AA (OR = 1.11, 95 % CI 0.93–1.32 P = 0.000 for heterogeneity) or GG versus AA OR = 1.19; 95 % CI 0.98–1.41 P = 0.000 for heterogeneity) (Fig. 4). Ten out of 42 studies included the association of the GSTP1 Ile105Val genotypes and lung caner risk stratified by gender (Male and Female) (Table 5). For Male population (9 studies) or female population (9 studies), significantly increased risks were not observed for both (GA ? GG) versus AA or GG versus AA (Fig. 5).
Table 2 Summary ORs for various contrasts of GSTP1 Ile105Val gene polymorphisms in this meta-analysis Subgroup analysis Total
Asian
Caucasian
Mixed population
42
1.04(0.96–1.12) 0.084
12,304/ 15,729
1.05(0.99–1.10) 0.009 0.009#
G/G vs. A/A
18
1.22(1.16–1.59) 0.016
(G/A ? G/G) vs. A/A
3,175/ 5,516
1.24(1.12–1.37) 0.233
G/G vs. A/A
19
0.94(0.87–1.03) 0.090
(G/A ? G/G) vs. A/A
7,378/ 8,397
0.97(0.91–1.04) 0.260
G/G vs. A/A
7
1.14(0.98–1.33) 0.090
(G/A ? G/G) vs. A/A
1,751/ 1,816
1.06(0.92–1.23) 0.094 0.158#
Gender Male
Female
G/G vs. A/A
9
0.93(0.82–1.05) 0.360
(G/A ? G/G) vs. A/A
2,301/ 2,646
0.97(0.88–1.08) 0.867
G/G vs. A/A (G/A ? G/G) vs. A/A
9 1,253/ 1,604
0.93(0.82–1.02) 0.000 0.97(0.86–1.09) 0.016 0.187#
Histological type SCC
AC
SCLC
G/G vs. A/A
14
0.94(0.83–1.06) 0.074
(G/A ? G/G) vs. A/A
1,961/ 5,391
0.99(0.89–1.10) 0.045
G/G vs. A/A
15
0.90(0.79–1.01) 0.035
(G/A ? G/G) vs. A/A
2,488/ 5,551
0.93(0.84–1.03) 0.359
G/G vs. A/A
9
1.04(0.78–1.12)0.168
(G/A ? G/G) vs. A/A
587/3,619
1.15(0.96–1.38) 0.965 0.000#
Smoking status Smoker
Nonsmoker
Publication bias Begg’s funnel plot and Egger’s test were performed to access the publication bias of literatures. Evaluation of publication bias for (GA ? GG) versus AA for all studies showed that the Egger test was significant (small cell lung cancer = 0.002). The funnel plots for publication bias (Fig. 6) also showed some asymmetry. For the subgroup analyses by ethnicity, the P value of Egger test was 0.022 for Asian population and 0.236 for Caucasian population. These results indicated the potential for publication bias. However, for the subgroup analyses by histology, the Egger test was also not significant (P = 0.247) and for the
G/G vs. A/A (G/A ? G/G) vs. A/A
Ethnicity
Sensitivity analyses A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled Ors were not materially altered (data not shown).
Contrast studies OR(95 %) Ph (case/control)
G/G vs. A/A
9
1.18(1.08–1.35) 0.360
(G/A ? G/G) vs. A/A
3,148/ 2,481
1.13(1.01–1.26) 0.582
G/G vs. A/A
11
1.19(0.98–1.41) 0.000
(G/A ? G/G) vs. A/A
898/1,622
1.11(0.93–1.32) 0.000
Ph P value of Q test for heterogeneity test #
Total Ph for the (G/A ? G/G) vs. A/A
subgroup analyses by smoking status, the P value of Egger test was 0.125 (figure not shown).
Discussion It is well recognized that there is a range of individual susceptibility to the same kind of cancer even with
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Fig. 2 Forest plot (random-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/ A ? G/G) vs. A/A. The OR was considered to be statistically significant if the 95 % CI did not overlap with 1. Each box represents
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the OR point estimate, and its area is proportional to the weight of the study. The diamond (and broken line) represents the overall summary estimate, with CI represented by its width. The unbroken vertical line is set at the null value (OR = 1.0)
Mol Biol Rep Table 3 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by histological types of lung cancer First author-year
Dzian A-2012 Ada AO-2011
Ethnicity (country of origin)
Histology (SCC/AC/SCLC)
Caucasian (Slovak)
AC SCC
Caucasian (Turkey)
Caucasian (Spain)
G/G
A/A
A/G
G/G
59
46
13
153
115
22
56
45
11
153
115
22
AC
40
19#
133
98#
SCC
37
29#
133
98#
18
#
14
133
98#
10
#
104
143#
104 104
143# 143#
AC SCC SCLC
A/A
Controls
A/G
SCLC Gervasini G-2010
Lung cancer cases
6
#
26 6
23 9#
Yoon KA-2008
Asian (Korea)
AC
110
54
9
133
73
7
Larsen JE-2006
Caucasian (Australia)
AC
225
225
48
273
269
84
Miller DP-2006
Caucasian (USA)
Liang G-2005 Schneider J-2004
Asian (China) Caucasian (Germany)
SCC
230
213
51
273
269
84
AC
402
343
94
579
623
141
SCC
190
173
49
579
623
141 141
SCLC
69
80
27
579
623
AC
77
51
5
132
86
9
SCC
58
32
4
132
86
9
AC
48
43
21
298
254
70
SCC
81
75
27
298
254
70
SCLC
31
27
9
298
254
70
1
34
1
Wang J-2003
Asian (Japan)
AC
67
44
Lin P-2003
Asian (China)
AC
69
36#
226
106#
Caucasian (France)
SCC AC
47 32
36# 23
5
226 124
106# 120
20
SCC
54
46
15
124
120
20
SCLC
Stu¨cker I-2002
Lewis SJ-2002
Caucasian (UK)
23
17
8
124
120
20
AC
4
5
1
64
74
13
SCC
14
17
1
64
74
13
4
10
1
64
74
13
AC
121
32
7
184
65
8
SCC
58
14
1
184
65
8
SCLC
84
32
9
184
65
8
AC
21
15
6
154
144
34
SCC
29
20
3
154
144
34
SCLC
27
23
7
154
144
34
SCLC Kihara M-1999
To-Figueras J-1999
Jourenkova-MN-1998 Ryberg D-1997 #
Asian (Japan)
Caucasian (Spain)
Caucasian (France) Caucasian (Norway)
84
SCC
46
41
11
86
64
22
SCLC
21
25
6
86
64
22
AC
17
20
4
153
117
27
SCC
20
34
13
153
117
27
The number of the combined A/G and G/G genotypes
identical environmental exposure. Host factors, including polymorphisms of genes involved in carcinogenesis may have accounted for this difference. Therefore, genetic susceptibility to cancer has been a research focus in scientific community. Recently, genetic variants of the GSTP1 genes in the etiology of several cancers have drawn increasing attention. As it is known that individual studies
with a small sample size may have not enough statistical power to detect a small risk factor, in this meta-analysis, we involved a total of 12,304 lung cancer cases and 15,729 controls and explored the association between the GSTP1 Ile105Val gene polymorphisms and lung cancer risk and stratified by ethnicity, histological types of lung cancer, gender and the smoking status of the case and control
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Fig. 3 Forest plot (fixed-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by histological types of lung cancer
populations. Our results indicated that GSTP1 Ile105Val gene polymorphism was not significantly associated with the susceptibility to lung cancer (OR = 1.05, 95 % CI 0.99, 1.10). In the stratified analysis, a significant
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association was found in Asians and smokers, not in Caucasian or mixed population or non-smokers. Additionally, no significant association was found in Male, Female population, lung AC, SCC or SCLC population.
Mol Biol Rep Table 4 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by smoking status First author-year
Ethnicity (country of origin)
Smoking status
Lung cancer cases A/A
Ihsan R-2011
Asian (India)
Yoon KA-2008
Asian (Korea)
Miller DP-2006
Caucasian (USA)
A/G 23
0
102
41
8
54
9
77
55
7
165
45
3
179
31
3
Non-smoking Non-smoking
64
66
13
199
230
48
621
750
207
380
393
93
21
22
Non-smoking
47
73
Asian (China)
Non-smoking Smoking
66 69
36# 56#
Schneider J-2004
Caucasian (Germany)
Non-smoking
13
5#
Smoking Non-smoking Smoking Non-smoking
Asian (China)
Smoking Perera FP-2002 Kihara M-1999
Mixed (USA) Asian (Japan)
Non-smoking
7#
217
252#
37
27
52
19#
18
#
32
16#
23
#
8
20#
174
217#
32
#
122
54#
72
42
#
104
52#
7
#
14
16#
67
69#
52
190#
8
#
Smoking
27
44
Non-smoking
15
8
1
50
18
5
263
78
17
134
47
3
Smoking #
81 #
134
Non-smoking
90 54# 41#
220
15
#
68 81 51
178 30
Smoking Lin P-2003
G/G
33
Mixed (USA)
Caucasian (USA)
A/G
69
Liang G-2005
Wang Y-2003
A/A
Non-smoking
Wenzlaff AS-2005
Asian (Japan)
G/G
Smoking
Smoking
Wang J-2003
Controls
The number of the combined A/G and G/G genotypes
When stratified according to ethnicity, significantly increased risks were identified among Asians for the two Ile105Val genotype variants; however, no significant association was found in Caucasians or mixed population. These findings indicate that polymorphisms of the GSTP1 Ile105Val gene polymorphism may be important in specific ethnicity of lung cancer patients. Population stratification is an area of concern, and can lead to spurious evidence for the association between the marker and disease, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they live in [63]. In addition, in our meta-analysis the between-study heterogeneity existed in the overall population, and the subgroup of Asians. Therefore, additional studies are required to further validate ethnic differences in the effect of this functional polymorphism on lung cancer risk. Cigarette smoking is the major environment factor for lung cancer, and hundreds of carcinogens have been identified in cigarette smoke [64]. Besides genetic factors, smoking represents the highest risk factor associated with lung cancer. It is hypothesized that a large proportion of lung cancer susceptibility is determined by the balance between an individual’s capacity to activate and detoxify carcinogens in tobacco smoke. GSTs, which comprise one superfamily of phase II detoxification enzymes, detoxify
polycyclic aromatic hydrocarbons found in tobacco smoke by conjugating them with glutathione [65]. GSTP1 Ile105Val gene polymorphisms has been reported to result in an enzyme with reduced activity [66]. It is possible that deficient or reduced activity of these enzymes might result in an increased susceptibility to cancer. In the present study, most of all 42 studies did not include definite information on non-smoking due to the harsh inclusion criteria; however, only 11 eligible publications provided non-smokers information. In the subgroup analysis by smoking status, the significantly increased risks were found to be associated with the GSTP1 Ile105Val gene polymorphisms and lung cancer risk among smokers but not non-smokers, suggesting that there could be an interaction between cigarette smoking and GSTP1 Ile105Val gene polymorphisms. This is consistent with the hypothesis that reduced ability to detoxify tobacco carcinogens in ETS through the enzymatic activity of GSTP1 contributes to lung cancer susceptibility. However, the association between the extent of smoke exposure and lung cancer risk was unclear, and further studies with larger sample sizes are required to provide insights into the association. When subgroup analyses by pathological type were considered, no significant associations were also found in lung AC subgroup or SCC or SCLC subgroup. There are
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Mol Biol Rep Fig. 4 Forest plot (randomeffects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by smoking status of population
growing biological and epidemiological data to suggest that different lung cancer pathological subtypes, particularly the two most common, were distinct etiological entities that should be analyzed separately [67]. In the process of histological differentiation of lung cancer, GSTP1 Ile105Val gene polymorphisms may be not independent factor. Recent epidemiological and biochemical studies have suggested increased susceptibility to tobacco carcinogens in women compared to men [68–70]. The possible mechanism was due to the effect of circulation estrogens, which have been shown to induce expression of PAH-metabolizing enzymes, such as GSTS, CYP1A1, thereby increasing metabolic activation of carcinogens [71]. However, in our meta-analysis, we found that the effect of GSTP1 Ile105Val genotype was not observed among Females or Male populations. Sever genome-wide association studies (GWAS) in populations of European and Asian descent has been conducted for identifying multiple new lung cancer susceptibility loci [72–74]. Recently, Dong et al. [75] and Lan et al. [76] performed the GWAS in the smoking population and never-smoking population respectively [75, 76]. However,
123
the GSTP1 Ile105Val gene polymorphism was not found in these GWAS. Our data were consistent with the results of these previous GWAS, indicated that GSTP1 Ile105Val gene polymorphism was not significantly associated with the susceptibility to lung cancer. In the stratified analysis, no significant association was found in Male, Female population, lung AC, SCC, SCLC population, Caucasian, mixed population or non-smokers. However, a significant association was only found in Asians and smokers. Considering the limited included studies of never-smoking and the heterogeneity in our meta-analysis, our results should be interpreted with caution. Some limitations of this meta-analysis should be acknowledged. First, heterogeneity can interfere with the interpretation of the results of a meta-analysis. Although we minimized this likelihood by performing a careful search of published studies, using explicit criteria for a study’s inclusion and performing strict data extraction and analysis, significant interstudy heterogeneity nevertheless existed in nearly every comparison. The presence of heterogeneity can result from differences in the selection of controls, age distribution, and prevalence of lifestyle factors. Although most controls were selected from healthy
Mol Biol Rep Table 5 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by gender First author-year
Ethnicity (country of origin)
Gender (male/female)
Lung cancer cases A/A
Timofeeva M-2010
Caucasian (Germany)
Yoon KA-2008
Asian (Korea)
Sorensen M-2007
Caucasian (Denmark)
Male
G/G
A/A
A/G
G/G
187
163
44
331
365
83
Female
92
106
25
209
216
53
Female
165
45
3
179
31
3
Male
110
93
26
192
175
57
84
87
29
157
148
37
Female Miller DP-2006
A/G
Controls
Caucasian (USA)
Male
448
427
124
264
268
70
Larsen JE-2006
Caucasian (Australia)
Female Male
437 355
389 360
96 72
315 196
355 180
71 48
Female
38
36
Liang G-2005
Asian (China)
Chan EC-2005
Asian (China)
146
124
77
89
Male
98
70#
99
69#
Female
37
22#
33
26#
Male
42
18
2
98
37
4
3
10
0
14
9
0
89
54#
35
#
Female Lin P-2003
Asian (China)
Male Female
Wang Y-2003
Caucasian (USA)
Male Female
Kihara M-1999 #
Asian (Japan)
Male
74
149
78#
77
28#
#
102
135#
#
80
102#
20
106
75
107
263
78
17
184
56
8
The number of the combined A/G and G/G genotypes
Fig. 5 Forest plot (fixed-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by gender of population
123
Mol Biol Rep
4. 5.
6.
7.
8.
Fig. 6 Begg’s funnel plot of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A for all studies
populations, some studies had selected controls among friends or family members of lung cancer patients or patients with other diseases. Further, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings might be unpublished. Finally, our results were based on unadjusted estimates; a more precise analysis should have been conducted if individual data were available, which would have allowed us to adjust using other covariates, including age, ethnicity, family history, environmental factors, and lifestyle [77]. Despite these limitations, this meta-analysis suggests that the GSTP1 Ile105Val gene polymorphisms are not associated with lung cancer risk in overall population, however stratified analysis by ethnicity, histology, gender and smoking status, it only correlate with increased lung cancer susceptibility among Asians and smokers. Acknowledgments This work was supported in part by a Grant from ‘‘Twelve-Five Plan’’ the Major Program of Nanjing Medical Science and Technique Development Foundation (Molecular Mechanism Study on Metastasis and Clinical Efficacy Prediction of Nonsmall Cell Lung Cancer) (Lk-Yu) and Third Level Training Program of Young Talent Project of Nanjing Health (P-Zhan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
9.
10.
11.
12.
13.
14.
15.
16. 17.
18. Conflict of interest in this work.
The authors declare no any conflicts of interest 19. 20.
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GSTP1 Ile105Val polymorphism is associated with lung cancer risk among Asian population and smokers: An updated meta-analysis Chun-hua Xu • Qin Wang • Ping Zhan Qian Qian • Li-Ke Yu
•
Received: 18 March 2013 / Accepted: 13 February 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Many studies have examined the association between the GSTP1 Ile105Val (rs 1695) gene polymorphism and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed and CNKI database was searched for case–control studies published up to July 2012. Data were extracted and pooled odds ratios (OR) with 95 % confidence intervals (CI) were calculated. Ultimately, 42 studies, comprising 12,304 lung cancer cases and 15,729 controls were included. Overall, for G allele carriers (GA ? GG) versus homozygote AA, the pooled OR was 1.05 (95 % CI 0.99–1.10 P = 0.092 for heterogeneity), for GG versus AA the pooled OR was 1.04 (95 % CI 0.96–1.12 P = 0.084 for heterogeneity). In the stratified analysis by ethnicity, gender, histological types of lung cancer and smoking status, a significant association was found in Asians and smokers, not in Caucasian or mixed population, Male, Female population, lung AC, SCC, SCLC or nonsmokers. Publication bias was found by using the funnel plot and Egger’s test. Overall, there is no evidence showing a significant correlation between GSTP1 Ile105Val gene polymorphism and lung cancer risk in overall population, however stratified analysis by ethnicity, histology, gender
C–H. Xu and Q. Wang contributed equally to this work and should be considered as co-first authors. C. Xu P. Zhan Q. Qian L.-K. Yu (&) First Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing 210029, China e-mail: [email protected] Q. Wang Department of Critical Care Medicine, 81 Hospital of PLA, Nanjing, China
and smoking status, it correlate with increased lung cancer susceptibility among Asians and smokers. Keywords GSTP1 Polymorphism Lung cancer Susceptibility Meta-analysis
Introduction Lung cancer remains the most lethal cancer worldwide, despite improvements in diagnostic and therapeutic techniques [1]. Its incidence has not peaked in many parts of world, particularly in China, which has become a major public health challenge all the world [2]. The mechanism of lung carcinogenesis is not understood. Although smoking status is the single most important factor that causes lung cancer, host factors including genetic polymorphism, had garnered interest with regard to the study of the tumorigenesis of lung cancer [3]. Otherwise, accumulating studies have suggested that lung cancers occurring in never smokers have different molecular profiles. In this way, host genetic susceptibility is a very important factor in the development of lung cancer, contributing to the variation in individual cancer risk. The glutathione S-transferases (GST) are a family of phase II enzymes that, by means of conjugation with glutathione, metabolize carcinogenic compounds that are found in tobacco smoke, combustion products, and diet [4]. These enzymes are encoded by different gene loci that are known to present polymorphisms that may compromise protein functionality. Cytosolic GST enzymes occupy a key position in biological detoxification processes [5]. They are classified according to their genetic and biochemical properties like alpha (GSTA), mu (GSTM), theta (GSTT), pi (GSTP), and omega (GSTO) [6].
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Mol Biol Rep Fig. 1 The flow diagram of search strategy
GSTP1 (rs 1695), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity [6]. Therefore, individuals with reduced or loss of GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Thus, associations between genetic polymorphism and development of environmental cancer clearly indicate the increased need to elucidate the effects of various polymorphic genes on cancer susceptibility and adverse health outcomes [7]. The predominant homozygous genotypes, the heterozygous genotypes and the homozygous rare genotypes of the GSTP1 Ile105Val gene polymorphism are named the homozygous wild-type genotype (A/A), the heterozygote (A/G) and the homozygote (G/G), respectively. Recently, many studies have investigated the role of the GSTP1 Ile105Val gene polymorphism in lung cancer. However, the results of these studies remain inconclusive. A single study might not be powered sufficiently to detect a small effect of the polymorphisms on lung cancer, particularly in relatively small sample sizes. Further, some studies have not controlled for the potential confounding effect of smoking properly-the main risk determinant for lung cancer. Various types of study populations and study designs might also have contributed to these disparate findings. To clarify the effect of the GSTP1 Ile105Val gene polymorphism on the risk for lung cancer, we performed a meta-analysis of all eligible case–control studies that have
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been published and conducted the subgroup analysis by stratification according to the ethnicity source, histological types of lung caner, gender and smoking status of case and control population.
Materials and methods Publication search We searched for studies in the PubMed and CNKI (China National Knowledge Infrastructure) electronic databases to include in this meta-analysis, using the terms ‘‘GSTP1,’’ ‘‘glutathione S-transferase pi,’’ ‘‘polymorphism,’’ and ‘‘lung cancer.’’ An upper date limit of July 01, 2012 was applied; no lower date limit was used. The search was performed without any restrictions on language and was focused on studies that had been conducted in humans. We also reviewed the Cochrane Library for relevant articles. Concurrently, the reference lists of reviews and retrieved articles were searched manually. Only full-text articles were included. When the same patient population appeared in several publications, only the most recent or complete study was included in this meta-analysis. Inclusion criteria For inclusion, the studies must have met the following criteria: they (1) evaluated GSTP1 gene polymorphisms and lung cancer risk; (2) were case–control studies or nestedcase control study; (3) supplied the number of individual genotypes for the GSTP1 Ile105Val gene polymorphisms in
Mol Biol Rep Table 1 Distribution of GSTP1 Ile105Val genotypes among lung cancer cases and controls included in this meta-analysis First author-year
Ethnicity (country of origin)
Mean age of cases
Male/female ratio
Total sample size (case/control)
Lung cancer cases
Controls
A/A
A/G
G/G
A/A
A/G
G/G
Dzian A-2012
Caucasian (Slovak)
62.5
2.93
230/290
115
91
24
153
115
22
Ada AO-2011
Caucasian (Turkey)
56
9.65
213/231
133
80#
133
98#
Ihsan R-2011
Asian (India)
60.4
3.37
188/290
102
77
179
96
9 #
Gervasini G-2010
Caucasian (Spain)
66
N/A
115/302
53
50
Timofeeva M-2010
Caucasian (Germany)
45.1
1.75
638/1,300
279
260
Lam TK-2010
Mixed (USA)
66.3
3.99
474/382
236
238#
Yadav DS-2010 Cote ML-2009
Asian (India) Mixed (USA)
N/A 59.7
N/A N/A
101/221 504/527
54 112
47 251
Kumar M-2009
Asian (India)
39.8
4.06
93/2,253
48
Yue Z-2009
Asian (China)
N/A
N/A
102/102
64
Honma HN-2008
Caucasian (Brazil)
N/A
2.57
200/264
82
93
Sobti RC-2008
Asian (India)
56.9
6.19
151/151
78
68
Sreeja L-2008
Asian (India)
57.8
6.91
111/111
116
74
Yoon KA-2008
Asian (Korea)
57
N/A
213/213
165
45
3
Reszka E-2007
Caucasian (Poland)
N/A
N/A
404/410
108
106#
104 69
15 #
143
540
591
172
210#
136
134
132 128
89 244
39
6
150
94
36
2
64
35
3
25
105
129
30
5
62
83
6
21
134
67
10
179
31
3
120
131#
151 9
Yang M-2007
Asian (Korea)
55.4
2.08
671/318
198
103
16
248
93
12
Sorensen M-2007
Caucasian (Denmark)
N/A
1.23
430/767
194
180
55
349
323
94
Zhang T-2006
Asian (China)
N/A
N/A
121/121
59
46
16
81
33
7
Larsen JE-2006
Caucasian (Australia)
63.4
0.56
1103/627
501
484
110
273
269
84
Miller DP-2006
Caucasian (USA)
N/A
0.92
1,921/1,343
885
816
220
579
623
141
Cao YF-2005
Asian (China)
N/A
N/A
97/197
66
26
5
143
46
8
Wenzlaff AS-2005 Wenzlaff AS-2005
Caucasian (USA) Mixed (USA)
62.4 62.4
0.73 0.73
135/151 166/181
39 47
58 73
15 21
61 68
72 90
18 22
Liang G-2005
Asian (China)
N/A
2.84
227/227
135
83
9
132
86
9
Chan EC-2005
Asian (China)
N/A
4.76
75/162
45
28
2
112
46
4
Cote ML-2005
Caucasian (USA)
42.4
1.12
247/290
79
127
22
109
141
38 19
Cote ML-2005
Mixed (USA)
41.4
0.74
103/120
16
60
13
37
63
Liang GY-2004
Asian (China)
N/A
N/A
152/152
94
54
4
105
43
4
Yang P-2004
Mixed (USA)
N/A
N/A
237/234
94
110
31
104
90
39
Schneider J-2004
Caucasian (Germany)
64.4
9.61
446/622
198
186
62
298
254
70
Lin P-2003
Asian (China)
N/A
2.6
198/332
124
74#
226
106#
Reszka E-2003
Caucasian (Poland)
59.7
2.86
138/165
73
60
5
83
77
Wang J-2003
Asian (Japan)
56.5
1.8
112/119
67
44
1
84
34
1
Wang Y-2003
Caucasian (USA)
60.9
1.10
362/419
149
178
35
182
193
44
Nie L-2002
Asian (China)
N/A
N/A
158/168
89
59
10
98
58
12
Lewis SJ-2002
Caucasian (UK)
58
1.8
93/151
34
53
6
64
74
13
Perera FP-2002 Stu¨cker I-2002
Mixed (USA)
N/A
N/A
89/173
33
52#
77
81#
Katoh T-1999
Caucasian (France) Asian (Japan)
59.5 64.6
N/A N/A
251/264 47/122
120 34
101 13
30 0
124 93
120 24
20 5
Kihara M-1999
Asian (Japan)
62
N/A
358/257
278
86
18
184
65
8
To-Figueras J-1999
Caucasian (Spain)
N/A
N/A
164/332
83
64
17
154
144
34
Harris MJ-1998
Mixed
66
N/A
178/199
79
73
26
80
101
18
Jourenkova-MN-1998
Caucasian (France)
N/A
N/A
150/172
67
66
17
86
64
22
Ryberg D-1997
Caucasian (Norway)
62.3
N/A
138/297
53
63
22
153
117
27
#
5
The number of the combined A/G and G/G genotypes
N/A not applicable
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lung cancer cases and controls, respectively; and (4) demonstrated that the distribution of genotypes among controls were in Hardy–Weinberg equilibrium. Data extraction Information was extracted carefully from all eligible publications independently by two authors, based on the inclusion criteria above. Disagreements were resolved through a discussion between the two authors. The following data were collected from each study: first author’s surname, year of publication, ethnicity, total numbers of cases and controls, and numbers of cases and controls who harbored the GSTP1 Ile105Val genotypes, respectively. We did not contact the author of the primary study to request the information. Ethnicities were categorized as Asian, Caucasian, and mixed population. Histological type of lung cancer was divided to lung squamous carcinoma (SCC), adenocarcinoma (AC) and small cell lung cancer (SCLC) in our meta-analysis. The definition of smoking history is very complicated. The smoking histories covered different periods if changes in the number of cigarettes smoked per day or type of tobacco products occurred. According to the general standards, non-smokers were defined as subjects who had smoked less than 100 cigarettes in their lifetime. Although the precise definition of never-smoking status varied slightly among the studies, the smoking status was classified as non-smokers (or never smoker) and smokers (regardless of the extent of smoking) in our meta-analysis. We did not require a minimum number of patients for a study to be included in our metaanalysis. The data extraction and quality assessment were reported in previous meta-analysis [8–15]. Statistical analysis OR (odds ratios) with 95 % CIs were used to determine the strength of association between the GSTP1 Ile105Val polymorphisms and lung cancer risk. The pooled ORs for the risk associated with the GSTP1 Ile105Val genotype, the G allele carriers (GA ? GG) versus the wild-type homozygotes (AA), GG versus AA were calculated, respectively. Subgroup analyses were done by ethnicity, gender, histological types of lung cancer and smoking status. Heterogeneity assumptions were assessed by Chi square-based Q test [16]. A P value greater than 0.10 for the Q test indicated a lack of heterogeneity among the studies. If P value of Q test for heterogeneity test was greater than 0.10, the pooled OR estimate was performed using the fixed-effects model (the Mantel–Haenszel method) according to the calculation principle of STATA software [17]; otherwise, the random-effects model (the DerSimonian and Laird method) was used
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[18].One-way sensitivity analyses were performed to determine the stability of the results-each individual study in the meta-analysis was omitted to reflect the influence of the individual dataset on the pooled OR [19]. Potential publication biases were estimated by funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetrical plot suggests a publication bias. Funnel plot asymmetry was assessed by Egger’s linear regression test, a linear regression approach that measures the funnel plot asymmetry on a natural logarithm scale of the OR. The significance of the intercept was determined by t test, as suggested by Egger (P \ 0.05 was considered a statistically significant publication bias) [20]. All calculations were performed using STATA, version 11.0 (Stata Corporation, College Station, TX).
Results Study characteristics One hundred and eighty-nine potentially relevant citations were reviewed, and 42 publications [21–62] met the inclusion criteria and included in our meta-analysis (Fig. 1). Table 1 presents the principal characteristics of these studies. Cote ML and Wenzlaff AS’s study [42, 45] sorted the data for Caucasians and Asians; therefore, each group in the study was considered separately in the pooled subgroup analyses. Of the 42 publications, 36 were published in English and 6 were written in Chinese. The sample sizes ranged from 169 to 3,264. All cases were histologically confirmed. The controls were primarily healthy populations and matched for age, ethnicity, and smoking status, 15 studies were hospital-based control and 27 were population-based control. There were 18 groups of Asians, 19 groups of Caucasians, and 7 mixed populations. All polymorphisms in the control subjects were in Hardy–Weinberg equilibrium. Meta-analysis results Table 2 listed the main results of this meta-analysis. Overall, for the G allele carriers (GA ? GG) versus homozygote AA, the pooled OR for all studies combined 12,304 cases and 15,729 controls was 1.05 (95 % CI 0.99–1.10 P = 0.009 for heterogeneity) (Fig. 2), for GG versus AA the pooled OR was 1.04 (95 % CI 0.96–1.12 P = 0.084 for heterogeneity). For all studies in the meta-analysis, no significant risks were found for the G allele carriers (GA ? GG) versus homozygote AA or GG versus AA, and heterogeneity was not found in all studies.
Mol Biol Rep
In the stratified analysis by ethnicity, significant risks were found among Asians for (GA ? GG) versus AA (OR = 1.24, 95 % CI 1.12–1.37 P = 0.233 for heterogeneity) or GG versus AA (OR = 1.22; 95 % CI 1.16–1.59 P = 0.016 for heterogeneity). For Caucasians, significant risks were not found for (GA ? GG) versus AA (OR = 0.97, 95 % CI 0.91–1.04 P = 0.260 for heterogeneity) or GG versus AA (OR = 0.94; 95 % CI 0.87–1.03 P = 0.090 for heterogeneity). Sixteen out of 42 studies examined the association of the GSTP1 Ile105Val genotype and the risk of different histological types of lung cancer including SCC, AC and SCLC (Table 3). Among lung SCC, lung AC or SCLC, no significant increased risks were observed for both (GA ? GG) versus AA or GG versus AA (Fig. 3). Eleven out of 42 studies included the association of GSTP1 Ile105Val genotypes and lung caner risk stratified by smoking status (non-smokers or never smokers and smokers) (Table 4). For smokers, significantly increased risks were observed for (GA ? GG) versus AA (OR = 1.13, 95 % CI 1.01–1.26 P = 0.582 for heterogeneity) or GG versus AA (OR = 1.18; 95 % CI 1.08–1.35 P = 0.360 for heterogeneity). However, for non-smokers, no significant associations were observed for (GA ? GG) versus AA (OR = 1.11, 95 % CI 0.93–1.32 P = 0.000 for heterogeneity) or GG versus AA OR = 1.19; 95 % CI 0.98–1.41 P = 0.000 for heterogeneity) (Fig. 4). Ten out of 42 studies included the association of the GSTP1 Ile105Val genotypes and lung caner risk stratified by gender (Male and Female) (Table 5). For Male population (9 studies) or female population (9 studies), significantly increased risks were not observed for both (GA ? GG) versus AA or GG versus AA (Fig. 5).
Table 2 Summary ORs for various contrasts of GSTP1 Ile105Val gene polymorphisms in this meta-analysis Subgroup analysis Total
Asian
Caucasian
Mixed population
42
1.04(0.96–1.12) 0.084
12,304/ 15,729
1.05(0.99–1.10) 0.009 0.009#
G/G vs. A/A
18
1.22(1.16–1.59) 0.016
(G/A ? G/G) vs. A/A
3,175/ 5,516
1.24(1.12–1.37) 0.233
G/G vs. A/A
19
0.94(0.87–1.03) 0.090
(G/A ? G/G) vs. A/A
7,378/ 8,397
0.97(0.91–1.04) 0.260
G/G vs. A/A
7
1.14(0.98–1.33) 0.090
(G/A ? G/G) vs. A/A
1,751/ 1,816
1.06(0.92–1.23) 0.094 0.158#
Gender Male
Female
G/G vs. A/A
9
0.93(0.82–1.05) 0.360
(G/A ? G/G) vs. A/A
2,301/ 2,646
0.97(0.88–1.08) 0.867
G/G vs. A/A (G/A ? G/G) vs. A/A
9 1,253/ 1,604
0.93(0.82–1.02) 0.000 0.97(0.86–1.09) 0.016 0.187#
Histological type SCC
AC
SCLC
G/G vs. A/A
14
0.94(0.83–1.06) 0.074
(G/A ? G/G) vs. A/A
1,961/ 5,391
0.99(0.89–1.10) 0.045
G/G vs. A/A
15
0.90(0.79–1.01) 0.035
(G/A ? G/G) vs. A/A
2,488/ 5,551
0.93(0.84–1.03) 0.359
G/G vs. A/A
9
1.04(0.78–1.12)0.168
(G/A ? G/G) vs. A/A
587/3,619
1.15(0.96–1.38) 0.965 0.000#
Smoking status Smoker
Nonsmoker
Publication bias Begg’s funnel plot and Egger’s test were performed to access the publication bias of literatures. Evaluation of publication bias for (GA ? GG) versus AA for all studies showed that the Egger test was significant (small cell lung cancer = 0.002). The funnel plots for publication bias (Fig. 6) also showed some asymmetry. For the subgroup analyses by ethnicity, the P value of Egger test was 0.022 for Asian population and 0.236 for Caucasian population. These results indicated the potential for publication bias. However, for the subgroup analyses by histology, the Egger test was also not significant (P = 0.247) and for the
G/G vs. A/A (G/A ? G/G) vs. A/A
Ethnicity
Sensitivity analyses A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled Ors were not materially altered (data not shown).
Contrast studies OR(95 %) Ph (case/control)
G/G vs. A/A
9
1.18(1.08–1.35) 0.360
(G/A ? G/G) vs. A/A
3,148/ 2,481
1.13(1.01–1.26) 0.582
G/G vs. A/A
11
1.19(0.98–1.41) 0.000
(G/A ? G/G) vs. A/A
898/1,622
1.11(0.93–1.32) 0.000
Ph P value of Q test for heterogeneity test #
Total Ph for the (G/A ? G/G) vs. A/A
subgroup analyses by smoking status, the P value of Egger test was 0.125 (figure not shown).
Discussion It is well recognized that there is a range of individual susceptibility to the same kind of cancer even with
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Mol Biol Rep
Fig. 2 Forest plot (random-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/ A ? G/G) vs. A/A. The OR was considered to be statistically significant if the 95 % CI did not overlap with 1. Each box represents
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the OR point estimate, and its area is proportional to the weight of the study. The diamond (and broken line) represents the overall summary estimate, with CI represented by its width. The unbroken vertical line is set at the null value (OR = 1.0)
Mol Biol Rep Table 3 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by histological types of lung cancer First author-year
Dzian A-2012 Ada AO-2011
Ethnicity (country of origin)
Histology (SCC/AC/SCLC)
Caucasian (Slovak)
AC SCC
Caucasian (Turkey)
Caucasian (Spain)
G/G
A/A
A/G
G/G
59
46
13
153
115
22
56
45
11
153
115
22
AC
40
19#
133
98#
SCC
37
29#
133
98#
18
#
14
133
98#
10
#
104
143#
104 104
143# 143#
AC SCC SCLC
A/A
Controls
A/G
SCLC Gervasini G-2010
Lung cancer cases
6
#
26 6
23 9#
Yoon KA-2008
Asian (Korea)
AC
110
54
9
133
73
7
Larsen JE-2006
Caucasian (Australia)
AC
225
225
48
273
269
84
Miller DP-2006
Caucasian (USA)
Liang G-2005 Schneider J-2004
Asian (China) Caucasian (Germany)
SCC
230
213
51
273
269
84
AC
402
343
94
579
623
141
SCC
190
173
49
579
623
141 141
SCLC
69
80
27
579
623
AC
77
51
5
132
86
9
SCC
58
32
4
132
86
9
AC
48
43
21
298
254
70
SCC
81
75
27
298
254
70
SCLC
31
27
9
298
254
70
1
34
1
Wang J-2003
Asian (Japan)
AC
67
44
Lin P-2003
Asian (China)
AC
69
36#
226
106#
Caucasian (France)
SCC AC
47 32
36# 23
5
226 124
106# 120
20
SCC
54
46
15
124
120
20
SCLC
Stu¨cker I-2002
Lewis SJ-2002
Caucasian (UK)
23
17
8
124
120
20
AC
4
5
1
64
74
13
SCC
14
17
1
64
74
13
4
10
1
64
74
13
AC
121
32
7
184
65
8
SCC
58
14
1
184
65
8
SCLC
84
32
9
184
65
8
AC
21
15
6
154
144
34
SCC
29
20
3
154
144
34
SCLC
27
23
7
154
144
34
SCLC Kihara M-1999
To-Figueras J-1999
Jourenkova-MN-1998 Ryberg D-1997 #
Asian (Japan)
Caucasian (Spain)
Caucasian (France) Caucasian (Norway)
84
SCC
46
41
11
86
64
22
SCLC
21
25
6
86
64
22
AC
17
20
4
153
117
27
SCC
20
34
13
153
117
27
The number of the combined A/G and G/G genotypes
identical environmental exposure. Host factors, including polymorphisms of genes involved in carcinogenesis may have accounted for this difference. Therefore, genetic susceptibility to cancer has been a research focus in scientific community. Recently, genetic variants of the GSTP1 genes in the etiology of several cancers have drawn increasing attention. As it is known that individual studies
with a small sample size may have not enough statistical power to detect a small risk factor, in this meta-analysis, we involved a total of 12,304 lung cancer cases and 15,729 controls and explored the association between the GSTP1 Ile105Val gene polymorphisms and lung cancer risk and stratified by ethnicity, histological types of lung cancer, gender and the smoking status of the case and control
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Mol Biol Rep
Fig. 3 Forest plot (fixed-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by histological types of lung cancer
populations. Our results indicated that GSTP1 Ile105Val gene polymorphism was not significantly associated with the susceptibility to lung cancer (OR = 1.05, 95 % CI 0.99, 1.10). In the stratified analysis, a significant
123
association was found in Asians and smokers, not in Caucasian or mixed population or non-smokers. Additionally, no significant association was found in Male, Female population, lung AC, SCC or SCLC population.
Mol Biol Rep Table 4 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by smoking status First author-year
Ethnicity (country of origin)
Smoking status
Lung cancer cases A/A
Ihsan R-2011
Asian (India)
Yoon KA-2008
Asian (Korea)
Miller DP-2006
Caucasian (USA)
A/G 23
0
102
41
8
54
9
77
55
7
165
45
3
179
31
3
Non-smoking Non-smoking
64
66
13
199
230
48
621
750
207
380
393
93
21
22
Non-smoking
47
73
Asian (China)
Non-smoking Smoking
66 69
36# 56#
Schneider J-2004
Caucasian (Germany)
Non-smoking
13
5#
Smoking Non-smoking Smoking Non-smoking
Asian (China)
Smoking Perera FP-2002 Kihara M-1999
Mixed (USA) Asian (Japan)
Non-smoking
7#
217
252#
37
27
52
19#
18
#
32
16#
23
#
8
20#
174
217#
32
#
122
54#
72
42
#
104
52#
7
#
14
16#
67
69#
52
190#
8
#
Smoking
27
44
Non-smoking
15
8
1
50
18
5
263
78
17
134
47
3
Smoking #
81 #
134
Non-smoking
90 54# 41#
220
15
#
68 81 51
178 30
Smoking Lin P-2003
G/G
33
Mixed (USA)
Caucasian (USA)
A/G
69
Liang G-2005
Wang Y-2003
A/A
Non-smoking
Wenzlaff AS-2005
Asian (Japan)
G/G
Smoking
Smoking
Wang J-2003
Controls
The number of the combined A/G and G/G genotypes
When stratified according to ethnicity, significantly increased risks were identified among Asians for the two Ile105Val genotype variants; however, no significant association was found in Caucasians or mixed population. These findings indicate that polymorphisms of the GSTP1 Ile105Val gene polymorphism may be important in specific ethnicity of lung cancer patients. Population stratification is an area of concern, and can lead to spurious evidence for the association between the marker and disease, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they live in [63]. In addition, in our meta-analysis the between-study heterogeneity existed in the overall population, and the subgroup of Asians. Therefore, additional studies are required to further validate ethnic differences in the effect of this functional polymorphism on lung cancer risk. Cigarette smoking is the major environment factor for lung cancer, and hundreds of carcinogens have been identified in cigarette smoke [64]. Besides genetic factors, smoking represents the highest risk factor associated with lung cancer. It is hypothesized that a large proportion of lung cancer susceptibility is determined by the balance between an individual’s capacity to activate and detoxify carcinogens in tobacco smoke. GSTs, which comprise one superfamily of phase II detoxification enzymes, detoxify
polycyclic aromatic hydrocarbons found in tobacco smoke by conjugating them with glutathione [65]. GSTP1 Ile105Val gene polymorphisms has been reported to result in an enzyme with reduced activity [66]. It is possible that deficient or reduced activity of these enzymes might result in an increased susceptibility to cancer. In the present study, most of all 42 studies did not include definite information on non-smoking due to the harsh inclusion criteria; however, only 11 eligible publications provided non-smokers information. In the subgroup analysis by smoking status, the significantly increased risks were found to be associated with the GSTP1 Ile105Val gene polymorphisms and lung cancer risk among smokers but not non-smokers, suggesting that there could be an interaction between cigarette smoking and GSTP1 Ile105Val gene polymorphisms. This is consistent with the hypothesis that reduced ability to detoxify tobacco carcinogens in ETS through the enzymatic activity of GSTP1 contributes to lung cancer susceptibility. However, the association between the extent of smoke exposure and lung cancer risk was unclear, and further studies with larger sample sizes are required to provide insights into the association. When subgroup analyses by pathological type were considered, no significant associations were also found in lung AC subgroup or SCC or SCLC subgroup. There are
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Mol Biol Rep Fig. 4 Forest plot (randomeffects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by smoking status of population
growing biological and epidemiological data to suggest that different lung cancer pathological subtypes, particularly the two most common, were distinct etiological entities that should be analyzed separately [67]. In the process of histological differentiation of lung cancer, GSTP1 Ile105Val gene polymorphisms may be not independent factor. Recent epidemiological and biochemical studies have suggested increased susceptibility to tobacco carcinogens in women compared to men [68–70]. The possible mechanism was due to the effect of circulation estrogens, which have been shown to induce expression of PAH-metabolizing enzymes, such as GSTS, CYP1A1, thereby increasing metabolic activation of carcinogens [71]. However, in our meta-analysis, we found that the effect of GSTP1 Ile105Val genotype was not observed among Females or Male populations. Sever genome-wide association studies (GWAS) in populations of European and Asian descent has been conducted for identifying multiple new lung cancer susceptibility loci [72–74]. Recently, Dong et al. [75] and Lan et al. [76] performed the GWAS in the smoking population and never-smoking population respectively [75, 76]. However,
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the GSTP1 Ile105Val gene polymorphism was not found in these GWAS. Our data were consistent with the results of these previous GWAS, indicated that GSTP1 Ile105Val gene polymorphism was not significantly associated with the susceptibility to lung cancer. In the stratified analysis, no significant association was found in Male, Female population, lung AC, SCC, SCLC population, Caucasian, mixed population or non-smokers. However, a significant association was only found in Asians and smokers. Considering the limited included studies of never-smoking and the heterogeneity in our meta-analysis, our results should be interpreted with caution. Some limitations of this meta-analysis should be acknowledged. First, heterogeneity can interfere with the interpretation of the results of a meta-analysis. Although we minimized this likelihood by performing a careful search of published studies, using explicit criteria for a study’s inclusion and performing strict data extraction and analysis, significant interstudy heterogeneity nevertheless existed in nearly every comparison. The presence of heterogeneity can result from differences in the selection of controls, age distribution, and prevalence of lifestyle factors. Although most controls were selected from healthy
Mol Biol Rep Table 5 Distribution of GSTP1 Ile105Val genotypes among cases and controls stratified by gender First author-year
Ethnicity (country of origin)
Gender (male/female)
Lung cancer cases A/A
Timofeeva M-2010
Caucasian (Germany)
Yoon KA-2008
Asian (Korea)
Sorensen M-2007
Caucasian (Denmark)
Male
G/G
A/A
A/G
G/G
187
163
44
331
365
83
Female
92
106
25
209
216
53
Female
165
45
3
179
31
3
Male
110
93
26
192
175
57
84
87
29
157
148
37
Female Miller DP-2006
A/G
Controls
Caucasian (USA)
Male
448
427
124
264
268
70
Larsen JE-2006
Caucasian (Australia)
Female Male
437 355
389 360
96 72
315 196
355 180
71 48
Female
38
36
Liang G-2005
Asian (China)
Chan EC-2005
Asian (China)
146
124
77
89
Male
98
70#
99
69#
Female
37
22#
33
26#
Male
42
18
2
98
37
4
3
10
0
14
9
0
89
54#
35
#
Female Lin P-2003
Asian (China)
Male Female
Wang Y-2003
Caucasian (USA)
Male Female
Kihara M-1999 #
Asian (Japan)
Male
74
149
78#
77
28#
#
102
135#
#
80
102#
20
106
75
107
263
78
17
184
56
8
The number of the combined A/G and G/G genotypes
Fig. 5 Forest plot (fixed-effects model) of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A stratified by gender of population
123
Mol Biol Rep
4. 5.
6.
7.
8.
Fig. 6 Begg’s funnel plot of lung cancer risk associated with GSTP1 Ile105Val polymorphisms for the (G/A ? G/G) vs. A/A for all studies
populations, some studies had selected controls among friends or family members of lung cancer patients or patients with other diseases. Further, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings might be unpublished. Finally, our results were based on unadjusted estimates; a more precise analysis should have been conducted if individual data were available, which would have allowed us to adjust using other covariates, including age, ethnicity, family history, environmental factors, and lifestyle [77]. Despite these limitations, this meta-analysis suggests that the GSTP1 Ile105Val gene polymorphisms are not associated with lung cancer risk in overall population, however stratified analysis by ethnicity, histology, gender and smoking status, it only correlate with increased lung cancer susceptibility among Asians and smokers. Acknowledgments This work was supported in part by a Grant from ‘‘Twelve-Five Plan’’ the Major Program of Nanjing Medical Science and Technique Development Foundation (Molecular Mechanism Study on Metastasis and Clinical Efficacy Prediction of Nonsmall Cell Lung Cancer) (Lk-Yu) and Third Level Training Program of Young Talent Project of Nanjing Health (P-Zhan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
9.
10.
11.
12.
13.
14.
15.
16. 17.
18. Conflict of interest in this work.
The authors declare no any conflicts of interest 19. 20.
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