SULT1A1 638 G>A
The genome Aggregation Database (gnomAD) reports a global frequency of 31.26% for the variant A-allele (NIH).
SULT1A1 Gene Detail
The sulfotransferase 1A1 enzyme (SULT1A1) is involved in catalysing the sulfate conjugation of many hormones, neurotransmitters, drugs, and phenolic xenobiotic compounds. Endogenous substrates include the oestrogen metabolite, 2-methoxyestradiol. Sulfation allows oestrogen conjugates to be more easily excreted into the bile or urine, resulting in reduced levels of oestrogen exposure in target tissues.
Studies have demonstrated that the SULT1A1 638 G>A polymorphism may be associated with breast cancer risk, especially in carriers of the A-allele. Beneficial modulation of oestrogen metabolism can be accomplished through dietary and lifestyle modifications such as increasing fibre and reducing fat intake, increasing phytoestrogen intake, losing weight, and increasing exercise.
SULT1A1 638 G>A Arg213His
Cytosolic sulfotransferases (SULTs) are part of a superfamily of phase II detoxification enzymes involved in the metabolism of a wide variety of structurally diverse endo- and xenobiotics such as hormones and putative carcinogens.
Major subfamilies exist, such as SULT1 (phenols) and SULT2 (hydroxysteroids). These SULT enzymes function by catalysing the transfer of a sulfonyl group to nucleophilic sites of oestrogens to form water-soluble and biologically inactive oestrogen sulfates. These conjugates are then excreted into the bile or urine, resulting in reduced levels of oestrogen exposure in target tissues. Although SULTs are widely expressed in human tissues, including the liver, they do show tissue-specific distribution.
The Sulfotransferase Family 1A Member 1 (SULT1A1) gene, which is mainly expressed in the liver, encodes for the sulfotransferase 1A1 enzyme. It is involved in catalysing the sulfate conjugation of many hormones, neurotransmitters, drugs, and phenolic xenobiotic compounds. Endogenous substrates include iodothyronines and the antiangiogenic oestrogen metabolite, 2-methoxyestradiol. SULT1A1 is thought to have high activity towards environmental carcinogens; it is involved in the bioactivation of N-hydroxy heterocyclic and aromatic amines found in the environment, particularly in meat cooked at high temperatures and in tobacco smoke. The sulfation may produce an electrophile that can form adducts with cellular macromolecules including DNA, which, if not repaired, can lead to carcinogenesis.
The SULT1A1 gene is located on chromosome 16p12.1-p11.2 and contains nine exons. The 638 G>A (Arg213His / rs9282861) polymorphism is reportedly the most widely studied SNP within the SULT1A1 gene. It occurs within exon 7 where a G-to-A transition results in an arginine (Arg) to histidine (His) amino acid substitution. Functional studies have reported that the variant A-allele (His-allele / SULT1A1*2) is associated with lower sulfotransferase activity and thermal stability compared with the wild-type G-allele (Arg-allele / SULT1A1*1).
Due to its role in the sulfation of oestrogens and anti-oestrogens, SULT1A1 has been most extensively investigated in relation to breast cancer risk. Although some epidemiological studies have demonstrated that the 638 G>A polymorphism may be associated with breast cancer risk it seems that the SNP should particularly be considered for postmenopausal as well as Asian women. However, the results of these studies are conflicting and inconclusive.
Therefore, Forat-Yazdi et al. (2017) performed a meta-analysis including a total of 20 relevant case-control studies (11,077 cases and 14,798 controls) to determine the association between the 638 G>A polymorphism and breast cancer risk. Results indicated that overall there was a significantly increased risk for breast cancer in A-allele carriers. The stratified analysis for ethnicity revealed that this association was significant in the Asian population, but not in Caucasians. The authors have suggested that living in different environments and experiencing different gene-environment interactions may partly affect breast cancer susceptibility.
Interestingly, these results are inconsistent with a previous meta-analysis by Xiao et al. (2014), which did not report a significant association between the SULT1A1 Arg213His polymorphism and breast cancer risk. The current meta-analysis, however, is described as the most comprehensive and robust meta-analysis to explore and report the association between the SULT1A1 Arg213His polymorphism and breast cancer up to date (2017); the authors collected all 20 eligible studies, which include 13 studies used by Xiao et al. but also seven new cases-control studies.
Prolonged exposure to endogenous and exogenous oestrogens has been associated with a substantially increased risk of breast cancer. Prolonged oestrogen exposure is said to cause direct genotoxic effects by inducing cell proliferation in oestrogen-dependent target cells (increasing the opportunity for the accumulation of random genetic errors), affecting cellular differentiation, and altering gene expression. A previous population-based case-control study of Chinese women, involving 1 102 cases (aged 25-64 years) and 1 147 age-matched population controls, found that women who carry the A allele have been associated with a greater risk for post-menopausal breast cancer, which is increased with higher BMI, and longer exposure to endogenous hormones.
Dietary and Lifestyle Modifications
Beneficial modulation of oestrogen metabolism can be accomplished through dietary and lifestyle modifications such as increasing fibre and reducing fat, increasing phytoestrogen intake, losing weight, and increasing exercise.
Dietary considerations to optimise oestrogen balance include:
- Maintain a healthy BMI since obesity increases endogenous oestrogen production by fat tissue, where the enzyme aromatase converts androgens into oestrogen.
- Include insoluble dietary fibre such as lignin (found in flaxseeds and the bran layer of grains, beans, and seeds) which can promote the excretion of oestrogens and make them less available for reabsorption and further metabolism. Dietary fibre intake can also increase serum concentrations of SHBG, thus reducing levels of free estradiol. Lignans may inhibit aromatase activity, thus decreasing the conversion of testosterone and androstenedione into oestrogens in fat and breast cells.
- Avoid excess consumption of simple carbohydrates as it raises blood glucose and insulin levels. Excess insulin in the bloodstream prompts the ovaries to secrete excess testosterone and reduces sex hormone binding globulin (SHBG) levels, thus increasing levels of free oestrogen.
- Phytoestrogens (such as isoflavones and lignans) may beneficially influence oestrogen metabolism by increasing plasma SHBG levels and decreasing aromatase activity.
Association between SULT1A1 Arg213His (rs9282861) Polymorphism and Risk of Breast Cancer: a Systematic Review and Meta-Analysis
Forat-Yazdi et al, 2017.