Sulfotransferase 1A1 Polymorphisms Research Articles

Combined effects of GSTO1 and SULT1A1 polymorphisms and cigarette smoking on urothelial carcinoma risk in a Taiwanese population.

Cigarette smoking is the main risk factor for urothelial carcinoma of the bladder (UCB). Glutathione S-transferase omega 1 (GSTO1) and sulfotransferase 1A1 (SULT1A1) have been reported to be associated with the metabolism of polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. The aim of the present study was to investigate the combined effects of polymorphisms in GSTO1 and SULT1A1 genes and cigarette smoking on UCB risk in a Taiwanese population. A total of 300 patients with histopathologically confirmed UCB and 233 cancer-free controls were recruited from the Department of Urology of Tung's Taichung Metro Harbor Hospital and Taipei Medical University Hospital. A comprehensive interview was conducted to collect personal information, including demographic characteristics and cigarette smoking status. A multivariate-adjusted logistic regression was performed to estimate the risk of UCB. A significantly increased risk of UCB was observed in ever smokers [odds ratio (OR) = 2.3]. The Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene were associated with a significantly increased risk of UCB, with ORs of 1.8 [95% confidence interval (CI) = 1.2-2.6] and 2.1 (95% CI = 1.6-4.5), respectively. Significantly increased UCB risks were found in heavy smokers with the Ala/Ala genotype of the GSTO1 gene (OR = 4.2) and the Arg/Arg genotype of the SULT1A1 gene (OR = 6.8). Furthermore, a significant synergistic effect in an additive model (OR = 3.5) between the GSTO1 Ala/Ala genotype and the SULT1A1 Arg/Arg genotype on UCB risk was observed. The present study provided epidemiological evidence for a significantly increased risk of UCB in ever smokers with the Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene.

Abstract 916: Functional significance of sulfotransferase 1A1 polymorphisms in the 3’ untranslated region in determination of enzymatic activity

Abstract SULT1A1 is the most highly expressed hepatic sulfotransferase and is involved in the biotransformation of a wide variety of endo-and xenobiotics. The inter-individual variation of SULT1A1 enzyme activity can markedly influence drug toxicity and/or treatment efficacy in the clinical setting. We and others have examined a common SNP in the coding region of SULT1A1 (Arg213His, SULT1A1*1/2), as well as several SNPs in the proximal promoter that were associated with altered enzymatic activity. However, the SNPs account for only a small proportion of variation of SULT1A1 activity in human populations. In order to identify SNPs that markedly affect SULT1A1 activity, we resequenced the 3’UTR of SULT1A1 in 97 liver samples. Direct sequencing revealed 2 SNPs (902A>G, 973C>T) in the 3’UTR and 1 SNP (1307G>A) in the 3’ flanking region. Interestingly, we found these SNPs are in absolute linkage disequilibrium and are closely associated with SULT1A1 expression and enzymatic activity. To further elucidate the important role of SNPs in 3’UTR, we performed haplotype analysis to predict the collective effects of functional genetic variants in the 3’ UTR regions, the SULT1A1*1/2 polymorphism and copy number variation on SULT1A1 enzymatic activity. Notably, two major haplotypes (ACGG and GTAA) were significantly correlated with SULT1A1 activity, Copy number did not influence on SULT1A1 activity in liver samples. 3’UTR SNPs are in linkage disequilibrium with SULT1A1*1/2 polymorphism, so to examine the effect of the SULT1A1*1/2 polymorphism, we performed haplotype-activity assay in 499 Caucasian and 129 African American subjects. Haplotype and regression analysis both strongly suggest that the 3’UTR SNPs are the pivotal predictor of SULT1A1 activity. MicroInspector predicts 3116C>T influences the binding of miR-631 to SULT1A1 3’UTR. Furthermore, in vitro luciferase reporter assays and overexpression of miRNA mimics and inhibitors indicated that SULT1A1 is a direct target of miR-631 and miR-631 differentially regulates the C and T alleles of rs1042157. The results suggest, for the first time, that allele-specific regulation of SULT1A1 by miR-631 contributes to the activity variation of SULT1A1 in population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 916.

Human NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms and urothelial cancer risk in Taiwan

To investigate whether the NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms are associated with urothelial cancer (UC) risk in Taiwan. In this study, 600 study subjects (including 300 UC patients and 300 cancer-free controls) were recruited from September 1998 to December 2005. We analyzed the NQO1 and SULT1A1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A comprehensive interview was conducted to collect information, including baseline characteristics and cigarette smoking status. We used an unconditional multivariate logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI). We found a significantly increased UC risk in study subjects with the NQO1 C/T and T/T genotypes (OR = 1.5; 95% CI: 1.03-2.1). A significantly increased UC risk was found in those with the SULT1A1 G/G genotype (OR = 2.0; 95% CI: 1.3-3.2). Subjects who had ever smoked with either the NQO1 C/T and T/T genotypes or the SULT1A1 G/G genotype had significantly increased UC risks, showing ORs of 3.0 and 5.3, respectively. Subjects carrying both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had a significantly increased UC risk (OR = 3.7; 95% CI, 1.4-9.7). Moreover, those who had ever smoked with both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had the highest UC risk (OR = 8.6; 95% CI: 2.5-29.7). These findings suggest that NQO1 and SULT1A1 polymorphisms are associated with the risk of UC, particularly among those who have ever smoked.

Impact of polymorphism in sulfotransferase gene on the risk of lung cancer

Sulfotransferases (SULTs) are very important multifunctional enzymes that catalyze sulfonate conjugation, which is an important pathway in the phase II metabolism of numerous endogenous and exogenous compounds. Sulfotransferase 1A1 (SULT1A1) is active toward a wide range of substrates, including environmental and tobacco carcinogens. This case-control study involved collection of peripheral blood samples (2–5 mL) of 103 lung cancer patients and 122 controls from North Indian subjects. The SULT1A1 polymorphism was determined by using a polymerase chain reaction–restriction fragment length polymorphism method. The association between polymorphisms in the SULT1A1 gene with the risk of lung cancer was estimated by computing odds ratios (OR) and 95% confidence intervals (95% CI), using a multivariate logistic regression analysis. We observed marginally increased risk for mutant genotype (AA) of SULT1A1 for lung cancer (OR = 1.4, 95% CI = 0.48–4.06). A statistically significant association was found for smokers between either of two SULT1A1 genotypes, GA (OR = 10.3, 95% CI = 3.48–31.78, P = 0.000002) or AA (OR = 3.9, 95% CI = 1.99–7.81, P = 0.0002), and lung cancer. The present study indicates that the SULT1A1 genotype may play an important role in the risk of developing lung cancer, especially in cigarette smokers.

A case–control study investigating the role of sulfotransferase 1A1 polymorphism in head and neck cancer

Sulfotransferases (SULT) 1A1 detoxify and bio-activate a broad spectrum of substrates including xenobiotics. The SULT1A1 gene possesses a G-->A polymorphism that results in an Arg to His substitution at codon 213, with the His allele having a low activity. The purpose of this study was to evaluate whether SULT1A1 Arg213His polymorphisms are risk factors for head and neck squamous cell carcinoma (SCCHN). A total of 124 consecutive primary SCCHN patients and 249 age- and sex-matched hospital controls were enrolled in this study. Genomic DNA was isolated from peripheral blood lymphocytes and genotyping was performed by PCR-RFLP. A comprehensive epidemiological interview was conducted on all participants to collect their lifestyle data. The His/His frequencies in cases and controls were 6.5% (8/123) and 3.6% (9/247), respectively (P=0.049). Multivariate logistic regression analysis showed a significant association of SCCHN and His/His genotype (OR=3.60; 95% CI=1.01-12.88). This association was stronger amongst older people, alcohol and low fruit consumers. The resulted SULT1A1 His/His genotype also associated with a higher risk of neck node positive status (OR=5.82; 95% CI=1.10-30.68). These preliminary findings show for the first time that the SULT1A1 His (213) allele is a possible risk factor for head and neck cancer development.

Association of SULT1A1 and UGT1A1 polymorphisms with breast cancer risk and phenotypes in Russian women

Estrogens are critical for breast cancer initiation and development. Sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) conjugate and inactivate both estrogens and their metabolites, thus preventing estrogen-mediated mitosis and mutagenesis. SULT1A1 and UGT1A1 are both polymorphic, and different alleles encode functionally different allozymes. We hypothesize that low-activity alleles SULT1A1*2 and UGT1A1*28 are associated with higher risk for breast cancer and more severe breast tumor phenotypes. We performed a case-control study, which included 119 women of Russian ancestry with breast cancer and 121 age-matched Russian female controls. We used PCR followed by pyrosequencing to determine the SULT1A1 and UGT1A1 genotypes. Allele UGT1A1*28 was present at a higher frequency than the wild-type UGT1A1*1 allele in breast cancer patients as compared to controls (P = 0.002, OR = 1.79, CI 1.23–2.63). Consistently, the frequency of genotypes that contain allele UGT1A1*28 in the homozygous or the heterozygous state was greater in breast cancer patients as compared with the frequency of the wild-type UGT1A1*1/*1 genotype (P = 0.003, OR = 4.00, CI 1.49–11.11 and P = 0.014, OR = 2.04, CI 1.14–3.57, respectively). Individuals carrying allele UGT1A1*28 in the homo-or heterozygous state had larger breast tumors (>2 cm) as compared to the group with high-activity genotypes (P = 0.011, IR = 3.44, CI 1.42–8.36). No association was observed between any of the SULT1A1 genotypes and breast cancer risk or phenotypes. Our data suggest that UGT1A1, but not SULT1A1, genotypes are important for breast cancer risk and phenotype in Russian women.

Genotypic and allelic frequencies of SULT1A1 polymorphisms in women receiving adjuvant tamoxifen therapy

Human sulfotransferase 1A1 (SULT1A1) is involved in the metabolism of a number of substances including 4-hydroxytamoxifen. It has been shown that patients who are homozygous for the variant SULT1A1 *2/*2 have lower catalytic activity. Previous data has suggested that patients with this particular genotype may be at a greater risk of developing breast cancer or not responding to tamoxifen therapy. To date, there is no data within the Hispanic population on the genotypic and allelic frequencies of the SULT1A1 gene. Two hundred and ninety-six patients were genotyped by either restriction fragment length polymorphism (RFLP) or Pyrosequencing for the SULT1A1 exon 7 polymorphism. The genotypic frequency was 0.47 (*1/*1), 0.40 (*1/*2) and 0.13 (*2/*2) in Caucasians and 0.37 (*1/*1), 0.45 (*1/*2) and 0.18 (*2/*2) in Hispanics. Although Hispanics have a higher genotypic frequency of variant genotypes this difference was not statistically significant (p=0.26). SULT1A1 genotype did not correlate with any prognostic or predictive markers associated with breast cancer. Future evaluations will assess the functional significance of this polymorphism on survival.

Sulfotransferase 1A1 polymorphism and gastric cancer risk: a pilot case-control study

Sulfotransferases (SULT) catalyse both the bioactivation and detoxification of a wide range of promutagens and carcinogens. The SULT1A1 gene possesses a G→A polymorphism that results in a Arg to His substitution at codon 213, and the His allele has been shown to have a low activity and thermal stability. To test the hypothesis that individuals carrying the variant allele may be at high risk of gastric cancer, we identified the SULT1A1 Arg213 His genotype by a PCR-based RFLP in a preliminary study of 76 gastric adenocarcinoma patients that underwent curative gastrectomy and 260 age and sex-matched controls from a medical centre in Rome. A comprehensive epidemiological interview was conducted on all participants to collect lifestyle data. The prognostic significance of the SULT1A1 Arg213 His polymorphism with respect to staging, differentiation and histological type of gastric cancer was also evaluated. The frequencies of His/His in cases and controls were 11.9% (9/76) and 5% (13/260), respectively ( P=0.025). After adjusting for substance use, age, gender and physical activity, individuals with His/His showed a 3.32 fold increased risk of developing gastric cancer compared to those with Arg/Arg (95% CI=1.17–9.45). This positive association was more pronounced amongst males, alcohol drinkers, current smokers and consumers of grilled/barbecued meat and, unexpectedly, amongst individuals with a high intake of fruit. A statistically significant association was also found between the diffuse type of gastric cancer and the heterozygous SULT1A1 genotype. Our preliminary findings suggest for the first time that the SULT1A1 His 213 allele may be important in the development of gastric cancer, with other factors modulating such effect.

Sulfotransferase 1A1 ( SULT1A1) polymorphism and breast cancer risk in Chinese women

Background: Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, catalyzes the sulfation of a variety of phenolic and estrogenic compounds. A functional polymorphism of the SULT1A1 gene has been implicated in a decreased activity and thermostability when the wild-type arginine ( Arg) at codon 213 is substituted by a histidine ( His). Methods: We investigated the association between the His allele and the risk breast cancer in 213 cases and 430 matched controls in Chinese women, and the interaction between His allele and endogenous estrogen and dietary mutagens exposure factors were also determined by use of logistic regression analysis. Results: There was no significant difference in genotypes between the cancer patients and control populations. However, the frequency of the His allele in cases (13.6%) were significant higher than that in controls (9.5%), P=0.03. Compared with women carrying the Arg/ Arg genotype, the adjusted odds ratio (OR) of Arg/ His was 1.48 (95% CI=0.59–3.31) and His/ His was 2.28 (95% CI=0.69–9.58), P trend was 0.04. The adjusted OR of Arg/ His + His/ His was 2.60 (95% CI=1.12–6.05). His allele strengthen the effect of endogenous estrogen exposure with interaction index r>1, and weaken the effect of heterocyclic amines and polycyclic aromatic hydrocarbons derived from dietary with interaction index r<1, both were multiplicative interaction model. Conclusions: Our findings suggest that the SULT1A1 His allele was positively associated with the risk of breast cancer in Chinese women. And there was interaction between SULT1A1 polymorphism and related exposure factors.