SULT 1 A 1 Arg 213 His Polymorphism and Lung Cancer Risk : a Meta-analysis

Sulfotransferases (SULTs) are involved in the phase II metabolism of endogenous and exogenous compounds including drugs, thyroid and steroid hormones, catecholamines and procarcinogenic agents (Falany, 1997; Richard et al., 2001). Sulfotransferase 1A1 (SULT1A1), an important member of this enzyme superfamily, has high activity towards a wide range of substrates including environmental and tobacco carcinogens. SULT1A1 catalyze the sulfonation of N-hydroxy derivatives of arylamines and heterocyclic amines, which are presented in tobacco smoke, to form more reactive DNA-damaging electrophiles (Ozawa et al., 1994; Chou et al., 1995). Sulfonation can also activate another major class of tobacco carcinogens, polycyclic aromatic hydrocarbons (PAHs) and nitro PAHs (Watabe et al., 1982; Surh et al., 1995; Arlt et al., 2002). Therefore, reduced activity of SULT enzymes may result in accumulation of potential carcinogens. Several single nucleotide polymorphisms have been identified in the SULT1A1 gene (Raftogianis et al.,


Introduction
Sulfotransferases (SULTs) are involved in the phase II metabolism of endogenous and exogenous compounds including drugs, thyroid and steroid hormones, catecholamines and procarcinogenic agents (Falany, 1997; RESEARCH COMMUNICATION SULT1A1 Arg213His Polymorphism and Lung Cancer Risk: a Meta-analysis Shao-Guang Liao & , Lu Liu & , Ying-Yi Zhang, Ying Wang, Ya-Jie Wang* 1997; Ozawa et al., 1998;Hirata et al., 2008).Among these, a common polymorphism (G638A) at codon 213 in exon 7 of SULT1A1 gene causes an Arg to His amino acid substitution.The mutation in the SULT1A1 gene would affect an individual's capacity to efficiently sulfate endogenous compounds, drugs and xenobiotics, and consequently result in an individual's susceptibility to cancer (Coughtrie et al., 1999;Raftogianis et al., 1999).Some studies have demonstrated that genetic polymorphisms of SULT1A1 Arg213His are associated with susceptibility to several cancer types including lung cancer (Wang et al., 2002;Wong et al., 2002;Han et al., 2004;Nowell et al., 2004;Bardakci et al., 2008).
Lung cancer is a major cause of cancer death related to tobacco smoke in the world (Greenlee et al., 2000).In recent years, several studies to address the association between SULT1A1 Arg213His polymorphism and lung cancer risk were conducted, with contradictory results.Liang's study (Liang et al., 2004) reported that the variant SULT1A1 genotype (638GA or AA) was associated with a significantly increased risk for overall lung cancer, while in Tamaki's study (Tamaki et al., 2011) no association

Identification of eligible studies
We performed an extensive search of studies that examined the association of the SULT1A1 polymorphisms with lung cancer.All eligible studies were identified by searching the PubMed database.The following terms were used: "SULT1A1" or ''sulfotransferase'', ''polymorphism(s)'', "lung cancer" or ''lung carcinoma''.No language or country restrictions were applied.The retrieved literatures were then read in their entirety to assess their appropriateness for the inclusion in this metaanalysis by the two authors (Liao and Liu) independently.References of cited articles were reviewed to identify additional studies not indexed by Medline.Included studies were required to meet the following criteria: (a) articles evaluating the association between SULT1A1 Arg213His polymorphism and lung cancer risk; (b)study designed as case-control; (c) sufficient data available to estimate an odds ratio (OR) with its 95% confidence interval (95% CI).

Data extraction
Information was carefully extracted from all eligible publications independently by two authors (Liao and Liu), according to the inclusion criteria.Disagreement was resolved by discussion between the authors.If these two authors could not reach a consensus, a third author was consulted to resolve the dispute and a final majority decision was made.The following variables were extracted from each study if available: first author's surname, publication year, country in which the study was performed, ethnicity of the study population, matching criteria, numbers of cases and controls, and genotype distributions in both cases and controls.

Statistical analysis
We calculated summary odd ratios (ORs) corresponding to a 95% confidence interval (CI) to assess the strength of association between SULT1A1 Arg213His polymorphism and lung cancer.And the pooled OR was calculated by a fixed-effects model (the Mantel-Haenszel method) when between-study heterogeneity was absent (MANTEL et al., 1959).Otherwise, a random-effects model (the DerSimonian and Laird method) (DerSimonian et al.,1986) was selected.The between-study heterogeneity was assessed by the χ2 test-based Q statistic (Cochran et al., 1954).A P value greater than 0.10 for the Q-test indicates a lack of heterogeneity among studies.
The OR and its 95%CI in each comparison was assessed in dominant (GA/AA vs. GG), additive (AA vs. GG) and recessive (AA vs. GG/GA) genetic models.In addition, subgroup analyses for ethnicity (mixed, Asian and Caucasian population), smoking status (smokers and non-smokers) and gender (males and females) were conducted.
The potential publication bias was examined visually in a funnel plot of log [OR] against its standard error (SE), and the degree of asymmetry was tested by Egger's test (P<0.05was considered a significant publication bias) (Egger et al., 1997).In the control populations, Hardy-Weinberg equilibrium (HWE) was tested.This meta-analysis was performed using the software STATA version 11.2.

Characteristics of eligible studies
A total of five publications (Wang et al., 2002;Liang et al., 2004;Pachouri et al., 2006;Arslan et al., 2009;Tamaki et al., 2011) containing 1,669 cases and 1,890 controls were included in this meta-analysis.Table 1 lists the main characteristics of these studies.Four of these studies (Wang et al., 2002;Liang et al., 2004;Pachouri et al., 2006;Arslan et al., 2009) presented SULT1A1 Arg213His polymorphism genotype distributions according to the smoking status (smokers and non-smokers).And three of these studies (Wang et al., 2002;Liang et al., 2004;Arslan et al., 2009) presented SULT1A1 Arg213His polymorphism genotype distributions according to the sex (males and females).All of the cases were histologically confirmed as lung cancer.Controls were mainly healthy or hospital-based populations.Genotype distributions in    the controls of all studies were in agreement with HWE, except one study (Pachouri et al., 2006).
Next, the association between the SULT1A1 Arg213His polymorphism and lung cancer risk was evaluated according to different smoking status and gender in dominant model.In the subgroup analysis on smoking status, the results were negative (Table 3).However, stratification by gender indicated that the SULT1A1 Arg213His polymorphism was associated with an increased risk of lung cancer in both females and males (females: OR = 1.72, 95%CI = 1.29-2.27,P=0.00; males: OR = 1.46, 95%CI = 1.19-1.78,P=0.00; Table 3; Figure 2).

Evaluation of publication bias
Funnel plot and Egger's test were performed to assess the publication bias.The shape of the funnel plot did not indicate any evidence of obvious asymmetry (Figure 3

Discussion
SULT1A1 gene, located in chromosome 16p12.1-p11.2,encodes the SULT1A1 enzyme which is an important enzyme in the metabolism of endogenous and exogenous carcinogens.The G638A polymorphism in SULT1A1 which causes an Arg to His amino acid substitution results in reduced enzyme activity and thermostability, and consequently results in an individual's susceptibility to cancer (Raftogianis et al., 1997;Coughtrie et al., 1999).Regarding the association between SULT1A1 Arg213His polymorphism and lung cancer susceptibility, five case-control studies were found by searching PubMed, with inconclusive results.To resolve these problems, a meta-analysis was performed.The result of this meta-analysis suggested that the SULT1A1 Arg213His polymorphism was not significantly associated with lung cancer susceptibility in all genetic models.However, in dominant model, there was a borderline increased risk for mutant genotype (GA/AA) for lung cancer.Furthermore, in dominant model of the subgroup analysis by ethnicity, increased risk was found in mixed population, while no association was detected in Asians and Caucasians populations.Further investigation may be needed to confirm the result.
Cigarette smoking is thought to be responsible for 90% of lung carcinomas in men and 78% in women (Shopland et al., 1991).Processed tobacco contains more than 3,000 compounds, including 30 carcinogens (Hecht, 1999).SULT1A1 was known to be involved in the metabolism of procarcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons, both of which are present in tobacco smoke.In some studies, smokers with His213 allele have been shown to possess higher risk of developing lung cancer (Wang et al., 2002;Liang et al., 2004).Thus, we perform a subgroup analysis for smoking status (smokers and non-smokers).Similarly, in dominant model, we found a borderline increased risk for mutant genotype (GA/AA) for lung cancer both in smokers and non-smokers.This result needs further large-scale studies to confirm.
The most important pathway involves in the formation of estrogen is sulfatase pathway which involves conversion of inactive estrone sulfate into active estrone (Wang et al., 2005).Sulfotransferases (SULT) sulfonate estrone to inactive estrone sulfate, whereas steroid sulfatase (STS) hydrolyzes estrone sulfate to estrone.Thus the SULT1A1 polymorphisms are believed to modulate susceptibility to estrogen-mediated carcinogenesis such as breast cancer (Jiang et al., 2010;Wang et al., 2010;Sun et al., 2011).Differential regulation of the SULT1A1 enzymes may also account for the difference in lung cancer risk between males and females.Hence, gender status was considered as a potential source of heterogeneity.In the subgroup analysis by gender of this meta-analysis, SULT1A1 Arg213His polymorphism was associated with an increased risk of lung cancer in both males and females in dominant model.Interestingly, when all the eligible studies were pooled into the meta-analysis, only a borderline increased risk for lung cancer in dominant model was found.That may because of two of these studies were excluded in this subgroup analysis for lacking related information.Therefore, the conclusion about this association should be further investigated.
However, there are still some limitations exist in this meta-analysis.Between-study heterogeneity, resulting from different defined controls or some other factors, may impact on the results of this analysis.The matching criteria of the control group, such as age, smoking status, and environment exposures, are different between studies.The varied risk of lung cancer in these different populations may impact on the results.And OR value was obtained without adjusting.More accurate OR should be adjusted by age, smoking status, gender and other factors.
In conclusion, no significant association between SULT1A1 Arg213His polymorphism and lung cancer risk was revealed in overall comparisons.And subgroup analysis on smoking status in dominant model also shows a negative result.However, subgroup analysis showed an elevated risk in mixed population and both males and females with variant His allele in dominant genetic model.Further detailed investigation with large numbers of worldwide participants is needed to clarify the role of this polymorphism in lung cancer.

Figure 1 .
Figure 1.Meta-Analysis of SULT1A1 Arg213His Polymorphism and Lung Cancer Risk.a) dominant model; b) additive model; c) recessive model

Figure
Figure 2. Meta-Analysis of SULT1A1 Arg213His Polymorphism and Lung Cancer Risk in Different Gender (Dominant Model) ) and the Egger's test suggested the absence of publication bias (Dominant model: P=0.35; Additive model: P=0.69; Recessive model: P=0.67).

Table 2 . Results of Meta-analysis for SULT1A1 Arg213His Polymorphism and Lung Cancer Risk Analysis
Cases/ controls Dominant model (GA/AA vs. GG) Additive model (AA vs. GG) Recessive model (AA vs. GG/GA)