PLoS ONE plos plosone PLoS ONE 1932-6203 Public Library of Science San Francisco, USA PONE-D-14-10111 10.1371/journal.pone.0106774 Research ArticleBiology and life sciencesEvolutionary biologyPopulation geneticsGenetic polymorphismGeneticsCancer geneticsOncogenesGenetic lociAllelesGenetics of diseaseGenetic predispositionHuman geneticsGenetic association studiesMutationMissense mutationSubstitution mutationMolecular geneticsMedicine and health sciencesEpidemiologyCancer epidemiologyEnvironmental epidemiologyEpidemiological methods and statisticsGenetic epidemiologyMedical humanitiesEvidence-based medicineClinical geneticsOncologyCancer risk factorsGenetic causes of cancerPhysical sciencesMathematicsStatistics (mathematics)Statistical methodsMeta-analysisResearch and analysis methodsResearch designCase-control studies Sulfotransferase SULT1A1 Arg213His Polymorphism with Cancer Risk: A Meta-Analysis of 53 Case-Control Studies A Meta-Analysis of SULT1A1 Arg213His and Cancer Risk XiaoJuanjuan1 ZhengYabiao1 ZhouYinghui1 ZhangPing1 WangJianguo1 ShenFangyuan1 FanLixia1 KolluriVijay Kumar1 WangWeiping1 YanXiaolong2* WangMinghua1* Department of Biochemical and Molecular Biology, Medical College, Soochow University, Suzhou, Jiangsu, China Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China WeiQing-Yi Editor Duke Cancer Institute, United States of America * E-mail: 47260934@qq.com (XLY); mhwang@suda.edu.cn (MHW)

The authors have declared that no competing interests exist.

Conceived and designed the experiments: XLY MHW WPW. Performed the experiments: JJX YBZ YHZ PZ. Analyzed the data: YBZ LXF. Contributed reagents/materials/analysis tools: JJX JGW FYS. Wrote the paper: JJX YBZ VKK.

 2014 1692014 9 9 e106774 1032014 3072014 2014 Xiao et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

The SULT1A1 Arg213His (rs9282861) polymorphism is reported to be associated with many kinds of cancer risk. However, the findings are conflicting. For better understanding this SNP site and cancer risk, we summarized available data and performed this meta-analysis.

 Methods

Data were collected from the following electronic databases: PubMed, Web of Knowledge and CNKI. The association was assessed by odd ratio (OR) and the corresponding 95% confidence interval (95% CI).

 Results

A total of 53 studies including 16733 cancer patients and 23334 controls based on the search criteria were analyzed. Overall, we found SULT1A1 Arg213His polymorphism can increase cancer risk under heterozygous (OR = 1.09, 95% CI = 1.01–1.18, P = 0.040), dominant (OR = 1.10, 95% CI = 1.01–1.19, P = 0.021) and allelic (OR = 1.08, 95% CI = 1.02–1.16, P = 0.015) models. In subgroup analyses, significant associations were observed in upper aero digestive tract (UADT) cancer (heterozygous model: OR = 1.62, 95% CI = 1.11–2.35, P = 0.012; dominant model: OR = 1.63, 95% CI = 1.13–2.35, P = 0.009; allelic model: OR = 1.52, 95% CI = 1.10–2.11, P = 0.012) and Indians (recessive model: OR = 1.93, 95% CI = 1.22–3.07, P = 0.005) subgroups. Hospital based study also showed marginally significant association. In the breast cancer subgroup, ethnicity and publication year revealed by meta-regression analysis and one study found by sensitivity analysis were the main sources of heterogeneity. The association between SULT1A1 Arg213His and breast cancer risk was not significant. No publication bias was detected.

 Conclusions

The present meta-analysis suggests that SULT1A1 Arg213His polymorphism plays an important role in carcinogenesis, which may be a genetic factor affecting individual susceptibility to UADT cancer. SULT1A1 Arg213His didn't show any association with breast cancer, but the possible risk in Asian population needs further investigation.

 This work was supported by the grants from the National Natural Science Foundation of China (Grant numbers 81071957 and 81000938), (http://www.nsfc.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Data AvailabilityThe authors confirm that all data underlying the findings are fully available without restriction. All data are included within the paper and its Supporting Information files. Introduction

Sulfotransferase (SULT) enzymes catalyze the sulfate conjugation of a broad range of substrates and play an important role in metabolism of endogenous and exogenous compounds including thyroid and steroid hormones, neurotransmitters, drugs and procarcinogens [1], [2]. There are many isoforms of the SULTs supergene family, each with different amino acid sequence identity and substrate specificity [3]. SULT1A1 is an important member of the sulfotransferase family involving in the pathogenic process of various cancers [3]–[5].

The SULT1A1 gene is located on chromosome 16p12.1–p11.2 [6]. Previous study indicated that exon 7 of the SULT1A1 gene contained a G to A transition at codon 213 (rs9282861) that causes an Arg to His amino acid substitution [4]. Some studies have shown that this genetic polymorphism leads to a decrease in enzymatic activity of SULT1A1 and the sulfonation efficiency thus associating with susceptibility to several cancers [7], [8]. Although the specific role of SULT1A1 Arg213His polymorphism in carcinogenesis has been investigated in numerous case-control studies, the results have been inconclusive, even conflictive. In order to give a comprehensive and precise result, we performed this meta-analysis study to analyze the association between this polymorphism and cancer risk.

 Materials and Methods Identification of eligible studies

The meta-analysis was conducted following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Checklist S1). In this study, we did an exhaustive literature search on studies that examined the association of the SULT1A1 gene polymorphisms with cancer risks. All eligible studies were identified by searching the following databases: PubMed, Web of Knowledge and China National Knowledge Infrastructure (CNKI, http://www.cnki.net/). The following terms were utilized: “sulfotransferase, SULT or SULT1A1”, “polymorphism, variation, variant or mutation” and “cancer or carcinoma”. In the CNKI database, we searched with these corresponding key words in Chinese characters. Included studies should meet the following criteria: (1) evaluating the association between SULT1A1 Arg213His polymorphism and cancer risk; (2) study designed as case-control; (3) sufficient data available to estimate an odd ratio (OR) with its 95% confidence interval (95% CI).

 Data extraction

Two investigators extracted data independently and reached consensus on the following characteristics of the selected studies: first author's name, the year of publication, ethnicity of the study population, matching criteria, number of participants, genotype distribution and control source.

 Statistical analysis

Hardy-Weinberg equilibrium was assessed by Chi-square test. Crude odd ratio (OR) and 95% confidence interval (CI) were used to estimate the association between SULT1A1 polymorphism and cancer susceptibility under the dominant model (Arg/His+His/His vs. Arg/Arg), recessive model (His/His vs. Arg/Arg+Arg/His), homozygous model (His/His vs. Arg/Arg), heterozygous model (His/Arg vs. Arg/Arg) and allelic model (His vs. Arg). The heterogeneity among the studies was evaluated by Q-test and I2 value ranging from 0% to 100% to describe the percentage of between-study variation caused by heterogeneity. P value for the Q-test less than 0.10 indicates existing heterogeneity among studies. And then the pooled OR was measured by a random effect model (the DerSimonian-Laird method). Otherwise, a fixed effect model (the Mantel-Haenszel method) was chosen.

Subgroup analyses were performed according to cancer type (breast cancer, colorectal cancer, urothelial cancer, prostate cancer, lung cancer, upper aero digestive tract (UADT) cancer, ovarian cancer and gastric cancer), ethnicity (Caucasian, East Asian, Indian and African) and source of controls (hospital based and population based). When heterogeneity was detected, a multivariable meta-regression analysis including cancer type, ethnicity, control source and year of publication to explore potential source of heterogeneity and sensitivity analysis were performed.

The potential publication bias was estimated using Egger's linear regression test by visual inspection of the funnel plot. P<0.05 was considered statistically significant, and all P values were two-sided. Analyses were performed using the software Review Manager 5.3 (Cochrane Collaboration), R software (www.r-project.org) and STATA 12.0 software (StataCrop).

 Results Characteristics of eligible studies

The flow diagram of literature search was given in Figure 1. A total of 91 studies focusing the association between the SULT1A1 Arg213His polymorphism and cancer risks were identified. 25 of them were ruled out because of unavailable data or repeated data. Thus, the allele and genotype frequencies of the SULT1A1 Arg213His polymorphism were extracted from 66 articles. However, 18 articles didn't meet with Hardy-Weinberg equilibrium and were abandoned (Excluded list S1). As a result, 53 studies of 48 articles, involving 16733 cases and 23334 controls were included in the pooled analyses [9]–[56].

10.1371/journal.pone.0106774.g001 Flow diagram of the study selection process.

The characteristics of studies included in the current meta-analysis are shown in Table 1. Among these studies, 13 were conducted for breast cancer, 10 for colorectal cancer, 7 for urothelial cancer, 5 for prostate cancer, 5 for lung cancer, 5 for UADT (upper aero digestive tract) cancer, 3 for ovarian cancer, 2 for gastric cancer and 1 for myeloid leukemia, multiple myeloma, and endometrial cancer, respectively. By ethnics, there were 27 studies of Caucasians, 11 studies of East Asians, 4 studies of Indians, 2 studies of Africans and 9 studies of mixed ethnics. By source of controls, 16 studies were population-based, 17 studies were hospital-based and 20 studies were not clear.

10.1371/journal.pone.0106774.t001 Characteristics of studies included in the meta-analysis.
First author Year Cancer type Ethnicity Source of Control Sample Size (Case/Control) Genotype Distribution (Case/Control) P for HWE
Arg/Arg Arg/His His/His
Seth 2000 Breast Caucasian Population 444/227 229/110 176/94 39/23 0.907
Steiner 2000 Prostate Caucasian Population 134/184 57/72 60/80 17/32 0.496
Bamber 2001 Colorectal Caucasian Mixed 226/293 96/137 104/124 26/32 0.885
Wang 2001 Lung Caucasian Population 463/485 195/226 201/196 67/63 0.148
Zheng 2001 Breast Mixed Population 155/328 55/148 71/136 29/44 0.368
Nowell 2002 Colorectal Mixed Population 130/301 48/101 67/145 15/55 0.973
Ozawa 2002 Urothelial East Asians Population 166/214 128/154 32/53 6/7 0.662
Sachse 2002 Colorectal Caucasian Population 490/593 217/275 209/255 64/63 0.944
Wong 2002 Colorectal Caucasian Unknown 383/402 175/178 179/190 29/34 0.239
Wu 2003 UADT East Asians Hospital 187/308 135/274 52/34 0/0 0.591
Tang 2003 Breast Mixed Unknown 103/133 50/79 42/47 11/7 1.000
Tsukino 2003 Urothelial East Asians Hospital 306/306 238/242 62/60 6/4 0.992
Zheng 2003 Urothelial Mixed Hospital 384/386 196/164 155/174 33/48 0.985
Chacko 2004 Breast India Hospital 140/140 76/95 56/41 8/4 0.986
Hung 2004 Urothelial Caucasian Hospital 201/214 121/116 72/88 8/10 0.422
Langsenlehner 2004 Breast Caucasian Population 498/499 201/224 250/212 47/63 0.515
Liang 2004 Lung East Asians Population 805/809 581/672 217/134 7/3 0.397
Nowell 2004 Prostate African Population 106/93 59/46 42/41 5/6 0.732
Nowell 2004 Prostate Caucasian Population 344/310 149/109 149/145 46/56 0.815
Cheng 2005 Breast East Asians Hospital 468/740 439/693 27/47 2/0 0.672
Jerevall 2005 Breast Caucasian Population 229/227 80/83 121/106 28/38 0.916
Lilla 2005 Breast Caucasian Population 419/884 198/374 169/403 52/107 0.995
Pereira 2005 Colorectal Mixed Unknown 42/100 15/45 23/44 4/11 0.999
Pereira 2005 Gastric Mixed Unknown 20/100 10/45 8/44 2/11 0.999
Pereira 2005 Myeloid leukemia Mixed Unknown 35/100 14/45 16/44 5/11 0.999
Pereira 2005 Multiple myeloma Mixed Unknown 28/100 7/45 15/44 6/11 0.999
Sellers 2005 Ovary Caucasian Hospital 454/542 197/236 194/237 63/69 0.735
Sillanpaa 2005 Breast Caucasian Population 480/478 145/147 229/221 106/110 0.313
Sun 2005 Colorectal Caucasian Population 109/666 43/266 27/303 39/97 0.778
Boccia 2006 UADT Caucasian Hospital 123/247 71/156 44/82 8/9 0.907
Chen 2006 Colorectal East Asians Population 83/343 67/301 15/41 1/1 0.950
Feng 2006 UADT East Asians Hospital 163/166 109/129 50/32 4/5 0.258
Boccia 2007 Gastric Caucasian Hospital 107/254 57/156 39/85 11/13 0.950
Holt 2007 Ovary African Population 33/127 21/67 10/48 2/12 0.735
Holt 2007 Ovary Caucasian Population 277/448 117/185 133/213 27/50 0.624
Lilla 2007 Colorectal Caucasian Population 504/603 212/263 225/259 67/81 0.404
Roupret 2007 Urothelial Caucasian Hospital 268/268 119/140 99/101 50/27 0.395
Hirata 2008 Endometrial Caucasian Hospital 150/165 68/103 59/52 23/10 0.619
Koike 2008 Prostate East Asians Hospital 126/119 94/85 32/32 0/2 0.875
Wang 2008 Urothelial East Asians Hospital 300/300 261/240 37/54 2/6 0.377
Arslan 2009 Lung Caucasian Population 106/271 50/162 52/99 4/10 0.554
Cleary 2010 Colorectal Caucasian Population 1164/1292 544/598 502/540 118/154 0.173
MERIE-GENICA 2010 Breast Caucasian Population 3139/5426 1381/2338 1332/2430 426/658 0.789
Syamala 2010 Breast India Population 359/367 254/271 87/90 18/6 0.894
Arslan 2011 Prostate Caucasian Population 104/151 55/91 38/54 11/6 0.846
Ihsan 2011 Lung India Population 188/290 123/153 50/116 15/21 0.988
Serrano 2011 Breast Caucasian Hospital 46/136 24/71 18/55 4/10 0.989
Tamaki 2011 Lung East Asians Hospital 192/203 120/132 70/68 2/3 0.211
Cui 2012 Urothelial East Asians Hospital 282/257 218/201 59/52 5/4 0.956
Eichholzer 2012 Colorectal Caucasian Population 424/819 183/389 193/354 48/76 0.940
Khvostova 2012 Breast Caucasian Population 335/530 47/166 164/261 124/103 1.000
Kotnis 2012 UADT India Unknown 109/194 60/132 43/60 6/2 0.232
Santos 2012 UADT Mixed Hospital 202/196 94/94 89/82 19/20 0.944
Overall Analysis

Table 2 showed the results of overall analysis and the subgroup analysis. The analyses on the full data set indicated a significant association of the SULT1A1 Arg213His polymorphism with cancer risk: heterozygous (OR = 1.09, 95% CI = 1.01–1.19, P = 0.035), homozygous (OR = 1.20, 95% CI = 1.04–1.39, P = 0.014), dominant (OR = 1.12, 95% CI = 1.03–1.22, P  =  0.008) (Figure S1), recessive (OR = 1.16, 95% CI = 1.02–1.32, P = 0.027) and allelic model (OR = 1.11, 95% CI = 1.04–1.20, P = 0.003), with high heterogeneity among studies (I2 = 63.1%, 62.6%, 68.5%, 58.3% and 73.7%, respectively, all P<0.001)(Table 3).

10.1371/journal.pone.0106774.t002 Overall and subgroup meta-analysis of the association between <italic>SULT1A1</italic> Arg213His polymorphism and cancer risk under genetic models.
Groups N Cases/Controls Heterozygous Homozygous Dominant Recessive Allelic
OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P
Total 53 16733/23334 1.09 [1.01, 1.19]a 0.035 1.20 [1.04, 1.39]a 0.014 1.12 [1.03, 1.22]a 0.008 1.16 [1.02, 1.32]a 0.027 1.11 [1.04, 1.20]a 0.003
Cancer type
Breast cancer 13 6815/10115 1.14 [0.97, 1.33]a 0.108 1.37 [1.01, 1.87]a 0.045 1.18 [1.00, 1.40]a 0.050 1.23 [0.96, 1.57]a 0.108 1.15 [1.00, 1.32]a 0.044
Colorectal cancer 10 3555/5412 1.05 [0.95, 1.15]b 0.354 1.13 [0.88, 1.45]a 0.352 1.06 [0.97, 1.15]b 0.224 1.13 [0.83, 1.52]a 0.439 1.08 [0.97, 1.19]a 0.169
Urothelial cancer 7 1907/1945 0.86 [0.74, 1.00]b 0.050 0.97 [0.56, 1.71]a 0.925 0.88 [0.71, 1.10]a 0.269 1.03 [0.63, 1.69]a 0.907 0.92 [0.73, 1.16]a 0.475
Prostate cancer 5 814/857 0.87 [0.70, 1.07]b 0.188 0.82 [0.44, 1.51]a 0.515 0.85 [0.69, 1.03]b 0.097 0.79 [0.58, 1.08]b 0.145 0.86 [0.74, 1.00]b 0.051
Lung cancer 5 1754/2058 1.19 [0.79, 1.80]a 0.404 1.19 [0.87, 1.63]b 0.269 1.21 [0.82, 1.79]a 0.344 1.15 [0.85, 1.56]b 0.357 1.18 [0.88, 1.58]a 0.279
UADT cancer 5 784/1111 1.62 [1.11, 2.35]a 0.012 1.39 [0.85, 2.26]b 0.185 1.63 [1.13, 2.35]a 0.009 1.28 [0.80, 2.05]b 0.307 1.52 [1.10, 2.11]a 0.012
Ovarian cancer 3 764/1117 0.96 [0.79, 1.17]b 0.697 0.97 [0.72, 1.32]b 0.857 0.96 [0.80, 1.16]b 0.695 0.99 [0.74, 1.32]b 0.944 0.98 [0.85, 1.12]b 0.746
Gastric cancer 2 127/354 1.16 [0.75, 1.80]b 0.510 1.81 [0.86, 3.81]b 0.12 1.26 [0.84, 1.91]b 0.264 1.73 [0.84, 3.57]b 0.139 1.29 [0.93, 1.78]b 0.126
Ethnicity
Caucasian 27 11621/16614 1.06 [0.97, 1.16]a 0.174 1.20 [1.01, 1.43]a 0.035 1.10 [1.00, 1.20]a 0.044 1.16 [0.99, 1.36]a 0.058 1.10 [1.01, 1.19]a 0.019
East Asian 11 3078/3765 1.22 [0.92, 1.61]a 0.175 1.12 [0.71, 1.79]b 0.626 1.21 [0.92, 1.61]a 0.176 1.10 [0.69, 1.75]b 0.697 1.18 [0.92, 1.52]a 0.187
Indian 4 796/991 1.09 [0.66, 1.80]a 0.748 2.25 [0.94, 5.37]a 0.067 1.19 [0.72, 1.96]a 0.500 1.93 [1.22, 3.07]b 0.005 1.25 [0.84, 1.85]a 0.274
African 2 139/220 0.75 [0.47, 1.21]b 0.239 0.60 [0.23, 1.58]b 0.299 0.73 [0.46, 1.15]b 0.173 0.68 [0.26, 1.75]b 0.420 0.77 [0.53, 1.11]b 0.158
Source of controls
Hospital based 17 3895/4718 1.17 [1.00, 1.38]a 0.056 1.38 [1.12, 1.68]b 0.002 1.21 [1.02, 1.43]a 0.029 1.31 [1.08, 1.59]b 0.006 1.19 [1.03, 1.38]a 0.020
Population based 16 8295/12176 0.94 [0.85, 1.03]a 0.200 0.98 [0.83, 1.17]a 0.855 0.96 [0.91, 1.02]b 0.162 1.02 [0.85, 1.24]a 0.825 0.98 [0.90, 1.06]a 0.584
10.1371/journal.pone.0106774.t003 The overall and subgroup heterogeneity test of the <italic>SULT1A1</italic> Arg213His polymorphism on cancer risk.
Groups Heterozygous Homozygous Dominant Recessive Allelic
I2 (%) P I2 (%) P I2 (%) P I2 (%) P I2 (%) P
Total 63.1 0.000 62.6 0.000 68.5 0.000 58.3 0.000 73.7 0.000
Cancer type
Breast cancer 67.1 0.000 79.4 0.000 75.9 0.000 72.7 0.000 80.7 0.000
Colorectal cancer 16.4 0.354 58.2 0.010 0.00 0.659 74.0 0.000 50.8 0.032
Urothelial cancer 20.6 0.272 62.7 0.013 57.9 0.027 54.0 0.042 73.0 0.001
Prostate cancer 0.00 0.719 53.8 0.070 12.9 0.332 45.8 0.117 47.5 0.107
Lung cancer 86.2 0.000 0.00 0.665 85.8 0.000 0.00 0.841 83.0 0.000
UADT cancer 68.5 0.013 44.9 0.142 69.1 0.012 42.0 0.160 72.1 0.006
Ovarian cancer 0.00 0.673 0.00 0.562 0.00 0.560 0.00 0.603 0.00 0.460
Gastric cancer 0.00 0.457 16.8 0.273 0.00 0.325 0.00 0.347 27.9 0.239
Ethnicity
Caucasian 51.5 0.001 72.7 0.000 62.5 0.000 70.9 0.000 74.4 0.000
East Asian 77.8 0.000 0.00 0.481 78.8 0.000 0.00 0.547 77.8 0.000
Indian 81.9 0.001 62.7 0.045 83.0 0.001 42.6 0.156 81.0 0.001
African 0.00 0.724 0.00 0.845 0.00 0.685 0.00 0.882 0.00 0.653
Source of controls
Hospital based 58.6 0.001 32.4 0.103 64.6 0.000 21.7 0.207 68.0 0.000
Population based 40.7 0.046 57.4 0.002 31.1 0.114 69.1 0.000 55.7 0.004
Subgroup Analyses

We analyzed the association in cancer type subgroup. SULT1A1 Arg213His polymorphism can increase cancer risks in the following cancer types: breast cancer (homozygous model: OR = 1.37, 95% CI = 1.01–1.87, P = 0.045; dominant model: OR = 1.18, 95% CI = 1.00–1.40, P = 0.050 and allelic model: OR = 1.15, 95% CI = 1.00–1.32, P = 0.044); UADT cancer (heterozygous model: OR = 1.62, 95% CI = 1.11–2.35, P = 0.012; dominant model: OR = 1.63, 95% CI = 1.13–2.35, P = 0.009 and allelic model: OR = 1.52, 95% CI = 1.10–2.11, P = 0.012). Forest plots of breast cancer risk and UADT cancer risk were shown in Figure 2 and Figure 3 separately.

10.1371/journal.pone.0106774.g002 Forest plot on the association between <italic>SULT1A1</italic> Arg213His polymorphism and breast cancer risk in homozygous model. 10.1371/journal.pone.0106774.g003 Forest plot on the association between <italic>SULT1A1</italic> Arg213His polymorphism and UADT cancer risk in dominant model.

Analyzed by ethnicity, a moderately increased risk was observed in Caucasians (homozygous model: OR = 1.20, 95% CI = 1.01–1.43, P = 0.035 and allelic model: OR = 1.10, 95% CI = 1.01–1.19, P = 0.019) and Indians (recessive model: OR = 1.93, 95% CI = 1.22–3.07, P = 0.005). No significant association was found in other ethnicities in any model.

By control source, significant association was observed in hospital based study, but not the population based study.

 Meta-regression analysis

To find potential source of heterogeneity, multivariable meta-regression analyses were conducted in total group and subgroups including cancer type, ethnicity, control source and publication year. In the breast cancer subgroup, ethnicity (heterozygous model, P = 0.027; recessive model, P = 0.020) and publication year (heterozygous model, P = 0.019; recessive model, P = 0.012) are significant sources of heterogeneity (Table S1). Other variables don't affect heterogeneity.

 Sensitivity analysis

The sensitivity analysis was constructed by repeating the meta-analysis sequentially removing each study. In the recessive model, two studies [26], [57] were found to affect the pooled OR and the heterogeneity when removed. The study conducted by Khvostova was focused on breast cancer and Sun's study was focused on colorectal cancer among Caucasians, so further sensitivity analyses were conducted in total data set and breast cancer, colorectal cancer and Caucasian subgroups after removing the two studies (Table 4 and Table S2). In total group, the heterogeneity was significantly decreased (I2 = 58.2, 42.2, 63.5, 33.1 and 66.4, respectively). In the subgroup sensitivity analyses, removing the two studies can significantly decrease the heterogeneity among studies, most I2 values less than 50%. And this polymorphism didn't show any obvious correlation with breast cancer risk (Figure 4). At last, we conducted the sensitivity analyses on the remaining studies and the result was stable.

10.1371/journal.pone.0106774.g004 Forest plot on the association between <italic>SULT1A1</italic> Arg213His polymorphism and breast cancer risk in homozygous model omitting Khvostova's study. 10.1371/journal.pone.0106774.t004 Meta-analysis in breast, colorectal and Caucasian subgroups after omitting studies of Khvostova and Sun.
Groups Heterozygous Homozygous Dominant Recessive Allelic
OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P OR (95% CI) P
Total 1.09 [1.01, 1.18]a 0.040 1.10 [0.97, 1.24]a 0.131 1.10 [1.01, 1.19]a 0.021 1.06 [0.96, 1.18]a 0.261 1.08 [1.02, 1.16]a 0.015
Cancer type
Breast cancer 1.05 [0.93, 1.19]a 0.400 1.11 [0.91, 1.35]a 0.312 1.07 [0.95, 1.20]a 0.256 1.07 [0.89, 1.30]a 0.469 1.06 [0.97, 1.15]a 0.219
Colorectal cancer 1.07 [0.97, 1.18]b 0.165 1.00 [0.86, 1.16]b 0.997 1.06 [0.97, 1.16]b 0.226 0.97 [0.84, 1.12]b 0.439 1.02 [0.96, 1.10]b 0.439
Ethnicity
Caucasian 1.01 [0.96, 1.07]b 0.690 1.07 [0.94, 1.21]a 0.308 1.05 [0.98, 1.13]a 0.169 1.04 [0.93, 1.17]a 0.470 1.05 [0.98, 1.11]a 0.160
Publication bias

Funnel plots and Egger's test were carried out to assess publication bias. The shapes of funnel plots indicated no obvious asymmetry (Figure 5). Egger's test found no publication bias in the heterozygous (P = 0.074); homozygous (P = 0.146); dominant (P = 0.076); recessive (P = 0.282) and allelic model (P = 0.081).

10.1371/journal.pone.0106774.g005 Begg's funnel plot of the Egger's test for publication bias of SULT1A1 Arg213His polymorphism and cancer risk.

(A) heterozygous model (B) homozygous model (C) dominant model (D) recessive model The horizontal line in the funnel plot indicates the fixed-effects summary estimate, whereas the sloping lines indicate the expected 95% confidence intervals for a given SE.

 Discussion

SULT1A1 enzyme encoded by SULT1A1 gene plays an important role in xenobiotic metabolism. The Arg213His polymorphism, the most widely studied polymorphism within SULT1A1 gene, can reduce enzyme activity and thermostability, and consequently results in an individual's susceptibility to cancer [7], [8].

There have been a few meta-analyses focusing on this mutation and cancer risk [58]–[60]. However, most of these analyses were conducted before the year 2012 and a new meta-analysis is needed to give a comprehensive conclusion due to the increasing data of case-control studies.

This present meta-analysis, including 16733 cases and 23334 controls from 53 case-control studies, explored the association between the SULT1A1 Arg213His polymorphism and cancer risk. This is the largest scale meta-analysis so far. Our results suggested that the SULT1A1 Arg213His was associated with UADT cancer risk. As the upper aero digestive tract is exposed to numerous potential carcinogens such as phenolic xenobiotics, polycyclic aromatic hydrocarbons and heterocyclic aromatic amines contained in cigarette smoking, environmental pollutants and some food, this result manifests that the mutation within SULT1A1 causes the low SULT1A1 activity and is associated with high susceptibility to cancers related with environment.

In the sensitivity analyses, the study conducted by Khvostova influences the pooled estimates and the heterogeneity most in breast cancer subgroup. And after removing this study, the significant association between SULT1A1 Arg213His and breast cancer risk became null (Figure 2 and Figure 4). We further checked data from Khvostova and observed the percentage of wild homozygous genotype in Khvostova's study was obviously lower than that in other studies thus causing great heterogeneity. At last a robust result was achieved and failed to reveal significant association in breast cancer subgroup. This result is similar to Wang, Lee and Jiang [61]–[63], but they found a positive association of this polymorphism with breast cancer susceptibility among Asians. While in our meta-analysis, we only recruited one paper focused on breast cancer among Asians because other papers on Asians deviate from HWE and were excluded. This is a limitation of this meta-analysis and more independent case-control studies conducted on Asians are needed to conclude a more comprehensive result.

In the ethnic subgroup analysis, we found that the genotype distributions of the SNP site are different in ethnic groups. When calculating the percentage of alleles in every ethnic, we found that His allele in Asians (9.58%) is significantly less than in Caucasians (35.2%). Different ethnicities may have different genetic backgrounds, thus causing different genotype frequencies in Asian and other ethnic groups which may influence cancer susceptibility.

Li and Kotnis have conducted meta-analyses focused on environment-related cancers, such as tobacco-related cancers and found cancer risk could be modulated by interaction between genetic variants and environmental factors [58], [59]. As exposed environmental factors are different according to cancer types, for example smoking leads to lung cancer, while the intake of meat influences breast cancer and colorectal cancer [64], [65] and our analysis took many kinds of cancer into account, we decided not to include environmental factors. Moreover, the definitions of exposed environmental factors were not consistent in the studies, which could cause great heterogeneity. Our estimates were based on crude OR values, not adjusted OR values, which may yield inaccurate calculation.

There were several sources bringing in heterogeneity, such as study design, age and sex distribution, and ethnicity. Meta-regression analysis was conducted to find source of heterogeneity. In the breast cancer subgroup, publication year could cause great heterogeneity and further attention was paid to years. We found all the recruited studies were carried out before 2005 or after 2010, and there were no studies between 2006 and 2009. The His allele was 29.6% in the studies before 2005 and 33.0% after 2010, which was significantly different (P = 0.02). This may be caused by the different study population, and needs more case-control studies to illustrate.

In conclusion, our meta-analysis suggests that the SULT1A1 Arg213His polymorphism may contribute UADT cancer risk. As the result was calculated through sampling statics and statistical difference is not the same as clinical difference, the result can be used for clinical reference, not for clinical diagnosis of cancer. Further detailed investigation with larger number of worldwide participants is needed to clarify the role of this polymorphism in cancer risk.

 Supporting Information

Forest plot on the association between SULT1A1 Arg213His polymorphism and overall cancer risk in dominant model.

(TIF)

The P-value of meta-regression in overall and breast cancer groups.

(DOCX)

Heterogeneity test after omitting studies of Khvostova and Sun.

(DOCX)

PRISMA 2009 Checklist.

(DOC)

Excluded studies list with reasons.

(XLS)

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