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Paraoxonase 1 genetic polymorphisms and susceptibility to breast cancer: A meta-analysis
Cancer Epidemiology 36 (2012) e101–e103
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Short communication
Paraoxonase 1 genetic polymorphisms and susceptibility to breast cancer: A meta-analysis Mostafa Saadat Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 September 2011 Received in revised form 24 October 2011 Accepted 26 October 2011 Available online 30 November 2011
Aim: The paraoxonase 1 gene (PON1, MIN: 168820) is a member of the multifactorial antioxidant enzyme paraoxonase family (EC 3.1.1.2). Two common functional single-nucleotide polymorphisms L55M (dbSNP: rs854560) and Q192R (dbSNP: rs662) have been identified in the coding region of PON1. Several studies have investigated the associations between polymorphisms of PON1 and susceptibility to breast cancer, but have yielded apparently conflicting results. We therefore carried out a meta-analysis of published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between PON1 gene variants and breast cancer risk. Method: Overall six eligible studies were identified. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using fixed and random-effect models. Results: In our meta-analysis, the presence of the R allele was associated with decreased risk of breast cancer (QR + RR compared to QQ genotype, summary OR = 0.57, 95% CI: 0.49– 0.67, P < 0.001). Both heterozygosity (OR = 1.32, 95% CI: 1.10–1.58, P = 0.002) and homozygosity (OR = 2.16, 95% CI: 1.75–2.68, P < 0.001) for the 55M allele were associated with increased risk of breast cancer. Also there was a significant linear trend in risk associated with zero, one, and two 55M alleles (x2 = 54.2, P < 0.001). Conclusion: The present study showed that PON1 M and Q alleles are associated with a higher risk of breast cancer. Individuals having MM and QQ genotypes have a lower level and lower detoxification activity of the PON1 enzyme, which may increase the vulnerability of the breast to genetic damage by reducing the ability to detoxify inflammatory oxidants, as well as dietary carcinogens. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Meta-analysis Paraoxonase 1 PON1 Susceptibility
1. Introduction The paraoxonase gene family (EC 3.1.1.2) is a multifactorial antioxidant enzyme that can not only detoxify insecticides and nerve gas, but also can destroy oxidized low-density lipoprotein. This gene family consists of at least three members and is located on human chromosome 7q21.3–22.1 [1,2]. Two common functional single-nucleotide polymorphisms, L55M (rs854560) and Q192R (rs662), have been identified in the coding region of the human PON1 gene (MIN: 168820). The L55M polymorphism has been noted to affect the enzyme concentration [2]. The Q192R polymorphism differs in its hydrolytic activities toward lipid peroxides [1]. Its ability to detoxify carcinogenic oxidative stress products has led researches to hypothesize that the PON1 polymorphisms might contribute to the increased susceptibility to breast cancer. In the past decade, several studies have investigated the associations between polymorphisms of PON1 and susceptibility to breast cancer [3–8]. However, these studies have yielded
E-mail addresses: [email protected], [email protected]. 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.10.015
apparently conflicting results. Such inconsistency could be partly due to insufficient power, the small effect of polymorphisms in low-penetrance PON1 gene on breast cancer risk, and false-positive results. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between PON1 gene variants and breast cancer risk. 2. Methods Studies published up to July 2011 with information on PON1 polymorphisms and breast cancer risk were identified using electronic databases, MEDLINE (National Library of Medicine, Washington, DC, USA), Scopus, EBSCOhost Research Databases, ProQuest, Scirus, DOAJ (Directory of Open Access Journals), Indian Science Abstract, Google Scholar, SAGE, Open J-Gate, High-Wire, JSTAGE, and SID (Scientific Information Database). Search terms were ‘‘breast cancer’’, polymorphisms, L55M, Q192R, paraoxonase, and PON1. Furthermore, references cited in the retrieved articles were screened to trace additional relevant studies. The metaanalysis was limited to published articles in the English language. Overall, six eligible studies were identified (Table 1) [3–8]. Articles
M. Saadat / Cancer Epidemiology 36 (2012) e101–e103
e102 Table 1 Studies used in the meta-analysis. Study (year)
Place
Genotypes of controls
L55M polymorphism Stevens et al. (2006) Antognelli et al. (2009) Naidu et al. (2010) Hussein et al. (2011)
USA Italy Malaysia Egypt
Study (year)
Place
USA Turkey USA Italy Malaysia Egypt
a
x2 for testing Hardy–Weinberg equilibrium.
**
P < 0.001.
LL
LM
MM
HWE
LL
LM
MM
202 188 126 35
223 125 109 23
58 231 17 42
0.09 157.2** 1.04 28.9**
176 107 159 19
230 115 178 21
77 325 50 60
Genotypes of controls
Q192R polymorphism Stevens et al. (2006) Ag˘ac¸han et al. (2006) Gallicchio et al. (2007) Antognelli et al. (2009) Naidu et al. (2010) Hussein et al. (2011)
QR
RR
HWEa
QQ
QR
RR
238 17 469 340 115 46
198 29 353 152 115 42
47 6 82 52 22 12
0.38 1.46 1.73 27.2** 0.81 0.25
259 17 38 484 200 51
182 4 15 50 158 41
42 12 5 13 29 8
Table 2 Summary of meta-analysis of case–control studies examining PON1 polymorphisms and breast cancer risk. Comparisons
df
Q-statistics
a b *
Genotypes of cases
QQ
selected for meta-analysis had no overlap of subjects with other studies. In all of the studies, the polymorphisms of L55M and Q192R were determined by restriction fragment length polymorphism/polymerase chain reaction (RFLP–PCR) assays. All studies were reviewed twice and data extracted using a standardized form. Data were collected on the authors, year of publication, country of origin, study design, source of control group (hospital-based, population-based), ethnicity, and numbers of PON1 genotypes (at codons 55 and 192) among cases and controls. A database according to the extracted information from each article was established. Table 1 lists the number of case and control groups for each genotype of the PON1 polymorphisms. In terms of geographical location, three, two, and one studies were performed in Europe and North America [3,5,6], Asia [4,7], and Africa [8], respectively. For the control group of each study, the observed frequencies of the PON1 genotypes were assessed for Hardy–Weinberg equilibrium (HWE) using the x2 statistic. To take into account the possibility of heterogeneity across the studies, a statistical test for heterogeneity was performed based on the Cochran’s Q statistic test, in which a P-value < 0.05 suggested significant heterogeneity between studies [9]. The association was measured using randomeffect or fixed-effect models according to the studies’ heterogeneity. The fixed-effects method assumes no significant heterogeneity
Q192R polymorphism All studies QR versus QQ 5 44.88* RR versus QQ 5 21.50* QR + RR versus QQ 5 50.99* All studies after excluding one studya QR versus QQ 4 9.53* RR versus QQ 4 2.64 QR + RR versus QQ 4 2.97 L55M polymorphism All studies LM versus LL 3 2.25 MM versus LL 3 4.18 All studies after excluding two studiesb LM versus LL 2 0.16 MM versus LL 2 1.34
Genotypes of cases a
OR
95% CI
P-value
0.88 0.60 0.57
0.42–0.69 0.46–0.79 0.49–0.67
<0.001 <0.001 <0.001
0.76 0.82 0.77
0.63–0.91 0.60–1.12 0.65–0.92
0.003 0.240 0.004
1.32 2.16
1.10–1.58 1.75–2.68
0.002 <0.001
1.23 1.70
0.99–1.52 1.24–2.45
0.066 <0.001
Study of Antognelli et al. (2009) was excluded. Two studies of Antognelli et al. (2009) and Hussein et al. (2011) were excluded. There is heterogeneity between studies P < 0.05.
between the results of the individual studies being pooled, whereas the random-effects method allows for such heterogeneity. The fixed-effects and random-effects methods were used by Mantel–Haenszel [9] and DerSimonian and Laird methods [10], respectively. 3. Results We identified six eligible studies, including 3943 subjects (1608 patients and 2335 healthy controls) in relation to the polymorphisms of PON1 and risk of breast cancer; these are summarized in Table 1 [3–8]. For the Q192R polymorphism, the presence of the R allele was associated with a reduced risk for breast cancer (Table 2), with an OR for QR + RR versus QQ of 0.57 (95% CI: 0.49–0.67, P < 0.001). However, there was significant statistical heterogeneity between studies in this analysis. In order to find the source of the heterogeneity, we excluded one study [6] in which its control group was not at HWE (x2 = 27.2, df = 1, P < 0.001). After excluding the above-mentioned study, the results showed a dramatic decrease in heterogeneity. ORs in the restricted analysis were similar to those in the overall analysis with an OR for QR + RR versus QQ of P < 0.001. (OR = 0.77, 95% CI: 0.65–0.92, P = 0.004). Concerning the L55M genetic polymorphism, four studies were included in the analysis [3,6–8]. There was no significant heterogeneity between the studies (Table 2). The presence of the M allele was associated with an increased risk for breast cancer. The ORs = 1.32 (95% CI: 1.10–1.58, P = 0.002) and 2.16 (95% CI: 1.75–2.68, P < 0.001), respectively, for LM versus LL and MM versus LL. Excluding two studies that were not at HWE [6,8], they gave similar results (Table 2). Also there was a significant linear trend in risk associated with zero, one, and two 55M alleles (x2 = 54.2, P < 0.001). 4. Discussion In this meta-analysis of published data, M and Q alleles of the PON1 gene were associated with an increased risk of breast cancer. Earlier studies have reported that the M variant decreases the stability of the PON1 enzyme, thus lowering the concentration of PON1 in the blood which subsequently affects the activity of the enzyme. The LM genotype was found to have a PON1 activity level between those of LL and MM genotypes [2]. On the other hand, it is suggested that the R allele may lead to the production of PON1 enzyme with higher detoxification activity against potentially carcinogenic products of oxidative stress and lipid peroxidation [1]. Therefore, in individuals having MM and QQ genotypes, lower
M. Saadat / Cancer Epidemiology 36 (2012) e101–e103
detoxification activity of the PON1 enzyme may increase the vulnerability of the breast to genomic damage by reducing the ability to detoxify inflammatory oxidants as well as dietary carcinogens. Our results are very similar to those recently reported by Liu and Liu in a meta-analysis of published data on the associations between breast cancer risk and polymorphisms in three obesityrelated genes, including PON1 [11]. Our analysis included one small study of Q192R [4] not included in the Liu and Liu meta-analysis, and while the point estimates for the summary OR for QR + RR versus QQ were virtually identical in our study (0.57) and in the Liu and Liu analysis (0.58), differences in the confidence intervals mean that the Liu and Liu result was reported as showing no association for the R allele with breast cancer risk. The results obtained by us and by Liu and Liu for the L55M polymorphism were entirely consistent. It should be noted that the close physical proximity of the L55M and Q192R polymorphisms should place them in linkage disequilibrium. We had no data about prevalence of different haplotypes among breast cancer patients and healthy controls. Further researches in this field are needed to determine the possible association between haplotypes of PON1 and risk of breast cancer. Previously it has been reported that some genetic polymorphisms may be associated with increased risk of some types of cancer only in some ethnic groups [12–16]. For example, the polymorphism of glutathione S-transferase T1 (GSTT1) is associated with increased risk of gastric cancer only among Caucasians [14]. In relation to polymorphism in XRCC1, it is reported that Arg399Gln was associated with lung cancer among Asian but not among Western countries [13]. Because of the small number of studies available for our meta-analysis, we could not explore associations according to ethnicity. A limitation of the present study is the small number of articles (n = 6) available for meta-analysis. Therefore, it should be stated that the results should be interpreted with caution. Conflict of interest The author has no financial or any non-financial competing interests.
e103
Acknowledgment This study was supported by Shiraz University. References [1] Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet 1993;3:73–6. [2] Leviev I, Deakin S, James RW. Decreased stability of the M54 isoform of paraoxonase as a contributory factor to variations in human serum paraoxonase concentrations. J Lipid Res 2001;42:528–35. [3] Stevens VL, Rodriguez C, Pavluck AL, Thun MJ, Calle EE. Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPSII nutrition cohort. Cancer Epidemiol Biomarkers Prev 2006;15:1226–8. [4] Ag˘ac¸han B, Yaylım I, Ergen HA, Arıkan S, Ku¨c¸u¨cu¨k S, Yılmaz H, et al. Is paraoxonase1 192 BB genotype risk factor for breast cancer? Adv Mol Med 2006;2:37–40. [5] Gallicchio L, McSorley MA, Newschaffer CJ, Huang HY, Thuita LW, Hoffman SC, et al. Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease. Cancer Detect Prev 2007;31:95–101. [6] Antognelli C, Del Buono C, Ludovini V, Gori S, Talesa VN, Crino` L, et al. CYP17GSTP1PON1 and GLO1 gene polymorphisms as risk factors for breast cancer: an Italian case–control study. BMC Cancer 2009;9:115. [7] Naidu R, Har YC, Taib NA. Genetic polymorphisms of paraoxonase 1 (PON1) gene: association between L55M or Q192R with breast cancer risk and clinicopathological parameters. Pathol Oncol Res 2010;16:533–40. [8] Hussein YM, Gharib AF, Etewa RL, ElSawy WH. Association of L55M and Q192R polymorphisms in paraoxonase 1 (PON1) gene with breast cancer risk and their clinical significance. Mol Cell Biochem 2011;351:117–23. [9] Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719–48. [10] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. [11] Liu C, Liu L. Polymorphisms in three obesity-related genes (LEPLEPR, and PON1) and breast cancer risk: a meta-analysis. Tumour Biol )2011;(September). doi: 10.1007/s13277-011-0227-9 [Epub ahead of print]. [12] Hu Z, Ma H, Chen F, Wei Q, Shen H. XRCC1 polymorphisms and cancer risk: a meta-analysis of 38 case–control studies. Cancer Epidemiol Biomarkers Prev 2005;14:1810–8. [13] Kiyohara C, Takayama K, Nakanishi Y. Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis. Lung Cancer 2006;54:267–83. [14] Saadat M. Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: a meta-analysis. Cancer Sci 2006;97:505–9. [15] Saadat M, Ansari-Lari M. Genetic polymorphism of glutathione S-transferase T1, M1 and asthma, a meta-analysis of the literature. Pak J Biol Sci 2007;10:4183–9. [16] Saadat M, Ansari-Lari M. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer, a meta-analysis of the literatures. Breast Cancer Res Treat 2009;115:137–44.
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Short communication
Paraoxonase 1 genetic polymorphisms and susceptibility to breast cancer: A meta-analysis Mostafa Saadat Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 September 2011 Received in revised form 24 October 2011 Accepted 26 October 2011 Available online 30 November 2011
Aim: The paraoxonase 1 gene (PON1, MIN: 168820) is a member of the multifactorial antioxidant enzyme paraoxonase family (EC 3.1.1.2). Two common functional single-nucleotide polymorphisms L55M (dbSNP: rs854560) and Q192R (dbSNP: rs662) have been identified in the coding region of PON1. Several studies have investigated the associations between polymorphisms of PON1 and susceptibility to breast cancer, but have yielded apparently conflicting results. We therefore carried out a meta-analysis of published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between PON1 gene variants and breast cancer risk. Method: Overall six eligible studies were identified. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using fixed and random-effect models. Results: In our meta-analysis, the presence of the R allele was associated with decreased risk of breast cancer (QR + RR compared to QQ genotype, summary OR = 0.57, 95% CI: 0.49– 0.67, P < 0.001). Both heterozygosity (OR = 1.32, 95% CI: 1.10–1.58, P = 0.002) and homozygosity (OR = 2.16, 95% CI: 1.75–2.68, P < 0.001) for the 55M allele were associated with increased risk of breast cancer. Also there was a significant linear trend in risk associated with zero, one, and two 55M alleles (x2 = 54.2, P < 0.001). Conclusion: The present study showed that PON1 M and Q alleles are associated with a higher risk of breast cancer. Individuals having MM and QQ genotypes have a lower level and lower detoxification activity of the PON1 enzyme, which may increase the vulnerability of the breast to genetic damage by reducing the ability to detoxify inflammatory oxidants, as well as dietary carcinogens. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Meta-analysis Paraoxonase 1 PON1 Susceptibility
1. Introduction The paraoxonase gene family (EC 3.1.1.2) is a multifactorial antioxidant enzyme that can not only detoxify insecticides and nerve gas, but also can destroy oxidized low-density lipoprotein. This gene family consists of at least three members and is located on human chromosome 7q21.3–22.1 [1,2]. Two common functional single-nucleotide polymorphisms, L55M (rs854560) and Q192R (rs662), have been identified in the coding region of the human PON1 gene (MIN: 168820). The L55M polymorphism has been noted to affect the enzyme concentration [2]. The Q192R polymorphism differs in its hydrolytic activities toward lipid peroxides [1]. Its ability to detoxify carcinogenic oxidative stress products has led researches to hypothesize that the PON1 polymorphisms might contribute to the increased susceptibility to breast cancer. In the past decade, several studies have investigated the associations between polymorphisms of PON1 and susceptibility to breast cancer [3–8]. However, these studies have yielded
E-mail addresses: [email protected], [email protected]. 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.10.015
apparently conflicting results. Such inconsistency could be partly due to insufficient power, the small effect of polymorphisms in low-penetrance PON1 gene on breast cancer risk, and false-positive results. We therefore performed a meta-analysis of the published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between PON1 gene variants and breast cancer risk. 2. Methods Studies published up to July 2011 with information on PON1 polymorphisms and breast cancer risk were identified using electronic databases, MEDLINE (National Library of Medicine, Washington, DC, USA), Scopus, EBSCOhost Research Databases, ProQuest, Scirus, DOAJ (Directory of Open Access Journals), Indian Science Abstract, Google Scholar, SAGE, Open J-Gate, High-Wire, JSTAGE, and SID (Scientific Information Database). Search terms were ‘‘breast cancer’’, polymorphisms, L55M, Q192R, paraoxonase, and PON1. Furthermore, references cited in the retrieved articles were screened to trace additional relevant studies. The metaanalysis was limited to published articles in the English language. Overall, six eligible studies were identified (Table 1) [3–8]. Articles
M. Saadat / Cancer Epidemiology 36 (2012) e101–e103
e102 Table 1 Studies used in the meta-analysis. Study (year)
Place
Genotypes of controls
L55M polymorphism Stevens et al. (2006) Antognelli et al. (2009) Naidu et al. (2010) Hussein et al. (2011)
USA Italy Malaysia Egypt
Study (year)
Place
USA Turkey USA Italy Malaysia Egypt
a
x2 for testing Hardy–Weinberg equilibrium.
**
P < 0.001.
LL
LM
MM
HWE
LL
LM
MM
202 188 126 35
223 125 109 23
58 231 17 42
0.09 157.2** 1.04 28.9**
176 107 159 19
230 115 178 21
77 325 50 60
Genotypes of controls
Q192R polymorphism Stevens et al. (2006) Ag˘ac¸han et al. (2006) Gallicchio et al. (2007) Antognelli et al. (2009) Naidu et al. (2010) Hussein et al. (2011)
QR
RR
HWEa
QR
RR
238 17 469 340 115 46
198 29 353 152 115 42
47 6 82 52 22 12
0.38 1.46 1.73 27.2** 0.81 0.25
259 17 38 484 200 51
182 4 15 50 158 41
42 12 5 13 29 8
Table 2 Summary of meta-analysis of case–control studies examining PON1 polymorphisms and breast cancer risk. Comparisons
df
Q-statistics
a b *
Genotypes of cases
selected for meta-analysis had no overlap of subjects with other studies. In all of the studies, the polymorphisms of L55M and Q192R were determined by restriction fragment length polymorphism/polymerase chain reaction (RFLP–PCR) assays. All studies were reviewed twice and data extracted using a standardized form. Data were collected on the authors, year of publication, country of origin, study design, source of control group (hospital-based, population-based), ethnicity, and numbers of PON1 genotypes (at codons 55 and 192) among cases and controls. A database according to the extracted information from each article was established. Table 1 lists the number of case and control groups for each genotype of the PON1 polymorphisms. In terms of geographical location, three, two, and one studies were performed in Europe and North America [3,5,6], Asia [4,7], and Africa [8], respectively. For the control group of each study, the observed frequencies of the PON1 genotypes were assessed for Hardy–Weinberg equilibrium (HWE) using the x2 statistic. To take into account the possibility of heterogeneity across the studies, a statistical test for heterogeneity was performed based on the Cochran’s Q statistic test, in which a P-value < 0.05 suggested significant heterogeneity between studies [9]. The association was measured using randomeffect or fixed-effect models according to the studies’ heterogeneity. The fixed-effects method assumes no significant heterogeneity
Q192R polymorphism All studies QR versus QQ 5 44.88* RR versus QQ 5 21.50* QR + RR versus QQ 5 50.99* All studies after excluding one studya QR versus QQ 4 9.53* RR versus QQ 4 2.64 QR + RR versus QQ 4 2.97 L55M polymorphism All studies LM versus LL 3 2.25 MM versus LL 3 4.18 All studies after excluding two studiesb LM versus LL 2 0.16 MM versus LL 2 1.34
Genotypes of cases a
OR
95% CI
P-value
0.88 0.60 0.57
0.42–0.69 0.46–0.79 0.49–0.67
<0.001 <0.001 <0.001
0.76 0.82 0.77
0.63–0.91 0.60–1.12 0.65–0.92
0.003 0.240 0.004
1.32 2.16
1.10–1.58 1.75–2.68
0.002 <0.001
1.23 1.70
0.99–1.52 1.24–2.45
0.066 <0.001
Study of Antognelli et al. (2009) was excluded. Two studies of Antognelli et al. (2009) and Hussein et al. (2011) were excluded. There is heterogeneity between studies P < 0.05.
between the results of the individual studies being pooled, whereas the random-effects method allows for such heterogeneity. The fixed-effects and random-effects methods were used by Mantel–Haenszel [9] and DerSimonian and Laird methods [10], respectively. 3. Results We identified six eligible studies, including 3943 subjects (1608 patients and 2335 healthy controls) in relation to the polymorphisms of PON1 and risk of breast cancer; these are summarized in Table 1 [3–8]. For the Q192R polymorphism, the presence of the R allele was associated with a reduced risk for breast cancer (Table 2), with an OR for QR + RR versus QQ of 0.57 (95% CI: 0.49–0.67, P < 0.001). However, there was significant statistical heterogeneity between studies in this analysis. In order to find the source of the heterogeneity, we excluded one study [6] in which its control group was not at HWE (x2 = 27.2, df = 1, P < 0.001). After excluding the above-mentioned study, the results showed a dramatic decrease in heterogeneity. ORs in the restricted analysis were similar to those in the overall analysis with an OR for QR + RR versus QQ of P < 0.001. (OR = 0.77, 95% CI: 0.65–0.92, P = 0.004). Concerning the L55M genetic polymorphism, four studies were included in the analysis [3,6–8]. There was no significant heterogeneity between the studies (Table 2). The presence of the M allele was associated with an increased risk for breast cancer. The ORs = 1.32 (95% CI: 1.10–1.58, P = 0.002) and 2.16 (95% CI: 1.75–2.68, P < 0.001), respectively, for LM versus LL and MM versus LL. Excluding two studies that were not at HWE [6,8], they gave similar results (Table 2). Also there was a significant linear trend in risk associated with zero, one, and two 55M alleles (x2 = 54.2, P < 0.001). 4. Discussion In this meta-analysis of published data, M and Q alleles of the PON1 gene were associated with an increased risk of breast cancer. Earlier studies have reported that the M variant decreases the stability of the PON1 enzyme, thus lowering the concentration of PON1 in the blood which subsequently affects the activity of the enzyme. The LM genotype was found to have a PON1 activity level between those of LL and MM genotypes [2]. On the other hand, it is suggested that the R allele may lead to the production of PON1 enzyme with higher detoxification activity against potentially carcinogenic products of oxidative stress and lipid peroxidation [1]. Therefore, in individuals having MM and QQ genotypes, lower
M. Saadat / Cancer Epidemiology 36 (2012) e101–e103
detoxification activity of the PON1 enzyme may increase the vulnerability of the breast to genomic damage by reducing the ability to detoxify inflammatory oxidants as well as dietary carcinogens. Our results are very similar to those recently reported by Liu and Liu in a meta-analysis of published data on the associations between breast cancer risk and polymorphisms in three obesityrelated genes, including PON1 [11]. Our analysis included one small study of Q192R [4] not included in the Liu and Liu meta-analysis, and while the point estimates for the summary OR for QR + RR versus QQ were virtually identical in our study (0.57) and in the Liu and Liu analysis (0.58), differences in the confidence intervals mean that the Liu and Liu result was reported as showing no association for the R allele with breast cancer risk. The results obtained by us and by Liu and Liu for the L55M polymorphism were entirely consistent. It should be noted that the close physical proximity of the L55M and Q192R polymorphisms should place them in linkage disequilibrium. We had no data about prevalence of different haplotypes among breast cancer patients and healthy controls. Further researches in this field are needed to determine the possible association between haplotypes of PON1 and risk of breast cancer. Previously it has been reported that some genetic polymorphisms may be associated with increased risk of some types of cancer only in some ethnic groups [12–16]. For example, the polymorphism of glutathione S-transferase T1 (GSTT1) is associated with increased risk of gastric cancer only among Caucasians [14]. In relation to polymorphism in XRCC1, it is reported that Arg399Gln was associated with lung cancer among Asian but not among Western countries [13]. Because of the small number of studies available for our meta-analysis, we could not explore associations according to ethnicity. A limitation of the present study is the small number of articles (n = 6) available for meta-analysis. Therefore, it should be stated that the results should be interpreted with caution. Conflict of interest The author has no financial or any non-financial competing interests.
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