COMT Val158Met (472 G>A)
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 36.9% and 44.91% respectively for the variant A-allele (NIH). A meta-analysis from Rai et al. (2017) reported that the frequency of the A (Met) allele vary greatly among the populations studied: frequency of A (Met) allele is reported as 56% in American, 50% in European, and 27% in Asian populations.
COMT Gene Detail
COMT is a phase II enzyme that conjugates and inactivates catechol oestrogens (such as 2- and 4-hydroxyoestrogens) by the transfer of a methyl group, so that it can be more easily excreted.
The Val158Met polymorphism has been associated with 3- to 4-fold decreased activity of the COMT enzyme. Deficient COMT activity may play an important role in hormone-related cancer susceptibility since the incomplete conjugation of catechol oestrogens may lead to its oxidation to form reactive quinone intermediates capable of DNA damage.
Ensure the adequate intake of nutrients that function as cofactors in the methylation of catechol oestrogens such as magnesium, folate, and vitamins B2, B6 and B12. It is also recommended to optimise dietary factors that support oestrogen balance: insoluble dietary fibre, complex carbohydrates (versus refined sources), antioxidants and curcumin.
COMT 472 G>A Val158Met
The catechol-O-methyltransferase (COMT) gene, located on chromosome 22q11 and containing 6 exons, encodes for two length variants of the COMT protein: a shorter soluble or cytoplasmic protein (S-COMT) and a longer membrane bound protein (MB-COMT). It is highly expressed in a variety of tissues, including liver, kidney, breast tissue, endometrium and red blood cells.
COMT is a phase II enzyme that plays a role in the inactivation / conjugation of catechol oestrogens, as well as catecholamines such as dopamine, adrenaline and noradrenaline. It is therefore not only essential for oestrogen metabolism, but also takes part in body functions such as feeling pain, reaction to stress or modifying mood.
The rs4680 polymorphism entails a single G to A base pair change in exon 4, which results in a valine (Val) to methionine (Met) amino acid change in codon 158 of the membrane-bound form of the protein (MB-COMT). A homozygous variant genotype (AA or Met/Met) has been associated with 3- to 4-fold decreased activity of the COMT enzyme. Since the unstable variant allele (Met) has been associated with decreased activity of COMT as compared to the wildtype allele (Val), these two forms are also called the COMT-L allele (low activity) and COMT-H allele (high activity), respectively. Both alleles are said to be co-dominant, i.e. heterozygous individuals (Val/Met) have an intermediate level of COMT activity.
This clinically functional polymorphism has been reported as risk factor for several disorders/diseases, namely schizophrenia, attention-deficit hyperactivity disorder, autism, drug abuse, posttraumatic stress disorder, and cancer. Reduced COMT activity is also thought to increase the sensitivity to harmful stimuli and thus lead to the increased risk of chronic pain.
Conjugation Of Catechol Eestrogens
COMT inactivates catechol oestrogens (such as 2- and 4-hydroxyoestrogens) by the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the m-hydroxy group of the catechol compound. This forms less polar, more water-soluble monomethyl ethers (or methoxy-oestrogens) that can be excreted more easily in the bile and urine. If the formation of these conjugates is incomplete, catechol oestrogens may be oxidised to form reactive quinone/semiquinone intermediates (particularly oestradiol 3,4-quinone) capable of free radical formation, or direct formation of depurinating DNA adducts. Several studies have suggested a protective role of the COMT higher activity isoform, as it can protect reactive oxygen induced DNA damage, that are produced by oestrogen oxidation.
It has been stated that methylated catechol oestrogens have little or no binding affinities for the typical oestrogen receptor, and that they lack oestrogenic activity in the uterus. Furthermore, a tumour-suppressor effect has been proposed for 2-methoxyoestradiol. The observed lack of carcinogenic activity of the 2-hydroxyoestrogens may be due to the faster rate of O-methylation; the most active conjugation pathway for catechol oestrogens is methylation, but they can also be conjugated by glucuronidation or sulfation.
Research regarding the rs4680 SNP’s association with breast cancer remains controversial. Since reactive catechol oestrogen metabolites have been recognized to contribute to breast carcinogenesis, deficient COMT activity may play an important role in breast cancer susceptibility.
An ongoing prospective case-control study amongst Chinese subjects (427 cases and 536 controls) reported a significantly increased risk for breast cancer amongst individuals homozygous for the A-allele (AA genotype). The authors believe that although heterozygous individuals for COMT may exhibit reduced enzymatic activity and impaired ability to detoxify substrates, the activity of other enzymes (such as GSTP1) may increase as a compensatory mechanism so that these heterozygous (GA) individuals showed no increased risk of breast cancer development.
A recent meta-analysis from Rai et al. (2017) considered 26 Asian case control studies (5 971 cases and 7 253 controls) to conclude that individuals homozygous for the A-allele (AA genotype) were at a significantly increased risk for breast cancer. Another meta-analysis from Qin et al. (2012) however, reported no significant associations between the COMT Val158Met polymorphism and breast cancer risk overall, neither when subgroup analyses were done for ethnicity, source of controls and menopausal status. They considered a total of 56 studies including 34 358 cases and 45 429 controls.
On the other hand, a previous study from Mitrunen et al. (2001) have found that subjects carrying the A-allele (low activity allele) tended to have a decreased risk of developing breast cancer. They have however reported an increased risk for postmenopausal women homozygous for the A-allele (AA) and on long-term (>30 months) use of oestrogen (4-fold increased risk), or for women carrying the A-allele and early age (<12 years) at menarche.
It is widely accepted that oestrogens are involved in the development of breast tumours, and that elevated lifetime exposure to endogenous and exogenous oestrogens increase the risk of breast cancer. In support of these views, early age at menarche, late menopause, and hormone replacement therapy (HRT) have been shown to increase breast cancer risk. Since the conversion of androgens to oestrogen takes place in adipose tissue for postmenopausal women, it is reasoned that postmenopausal obesity would result in higher levels of circulating oestrogen and increase the risk for breast cancer. This has indeed been the finding in a study from Lavigne et al. (1997), but not in the study from Mitrunen et al. (2001).
A previous study on the COMT Val158Met and breast cancer risk (Thompson et al. 1998) found that the COMT Val/Val genotype associated with increasing breast cancer risk in postmenopausal women. These data indicate the presence of complex interactions between COMT Val158Met and menopausal status in hormone-related cancers.
A case-control study of 800 postmenopausal Caucasian women found no contribution of the rs4680 polymorphism to increased breast cancer risk when analysed individually. The study did however confirm its hypothesis that individual susceptibility to breast cancer may be increased by the combined effects of the risk genotypes in oestrogen metabolic genes: the concurrent presence of CYP1B1 (rs1056836) and COMT (rs4680) high-risk genotypes (CG/GG and GA/AA, respectively) posed a 2-fold risk of breast cancer. Women with three high-risk genotypes CYP1B1 (rs1056836), COMT (rs4680) and MnSOD (rs4880 – TC/CC) were at a 12.2-fold increased breast cancer risk. Their results suggest that individual susceptibility to breast cancer incidence may be increased by combined effects of the high-risk genotypes in oestrogen metabolic genes.
Endometrial And Ovarian Cancer
Since research findings on the rs4680 polymorphism and risk of endometrial cancer is contradicting, Lin et al. (2013) performed a meta-analysis (8 studies and 5 109 subjects) in 2013. The authors found no association in the pooled analysis, although the stratified analysis revealed a significantly increased risk for endometrial cancer amongst postmenopausal women homozygous for the Val-allele (Val/Val). No differences amongst ethnic groups were detected.
In 2014, Liu et al. conducted a meta-analysis to determine if any association exists between COMT Val158Met and both ovarian and endometrial cancer. In total, 15 studies (1,293 cases and 2,647 controls for ovarian cancer and 2,174 cases and 2,699 controls for endometrial cancer) were included. No significant associations were found for either cancer type in the pooled analysis, neither in the stratified analyses.
Zahid et al. (2014) found that women with two low-activity alleles of COMT (AA) plus one or two high-activity alleles of CYP1B1 (CG/GG) had higher levels of oestrogen-DNA adducts and were more likely to have ovarian cancer. The authors reported the novel finding that the ratio of depurinating oestrogen-DNA adducts to oestrogen metabolites and conjugates is significantly elevated in women with ovarian cancer, compared to the ratio in age-matched female control subjects. These findings may indicate that oestrogen metabolism is unbalanced in ovarian cancer and suggest that the formation of oestrogen-DNA adducts plays a critical role in the initiation of ovarian cancer.
The COMT Val158Met polymorphism might be significantly associated with urological cancers, but there have been contrasting viewpoints. Chen et al. (2016) set out to determine whether any association between the Val158Met polymorphism and urological cancers exist. After analysing 14 eligible studies comprising 3,285 cases and 3,594 controls, the results of the meta-analysis suggest that bladder cancer instead of prostate cancer and kidney cancer could be significantly associated with the Val158Met polymorphism of the COMT gene.
Several molecular epidemiologic case-control studies have reportedly shown the potential role of COMT Val158Met polymorphism in the risk of lung cancer. However, the results remain inconclusive and controversial. A meta-analysis from Tan et al. (2014) found that the Val158Met polymorphism increased lung cancer risk among women (from six individual studies with a total of 4,043 subjects). No association was seen in the pooled analysis, neither when stratified for ethnicity. To the best of the authors’ knowledge, this was the first meta-analysis that has evaluated the relationship between the COMT Vall58Met polymorphism and the risk of lung cancer.
Dietary and Lifestyle Modifications
Overall, beneficial modulation of oestrogen metabolism can reportedly be accomplished through dietary and lifestyle modifications such as increasing fibre and reducing fat intake, increasing phytoestrogen intake, losing weight, and increasing exercise.
Obtaining the necessary nutrients to support the methylation pathways is considered essential as it promotes detoxification of oestrogens and provides for more beneficial metabolites of oestrogen:
- The methylation of catechol oestrogens by the COMT enzyme, necessary for its inactivation, requires magnesium in addition to SAM and as a cofactor.
- Folate is a precursor to SAM. It is important to note that some individuals may have a genetic polymorphism that interferes with their ability to metabolise folic acid to the active form utilised by the body (MTHFR 677 C>T). Supplement with a metabolically active form of folate that doesn’t require enzymatic conversion, such as L-5-methyl tetrahydrofolate, to ensure that these patients maintain adequate folate levels.
- Vitamins B2, B6 and B12 are crucial for DNA synthesis and repair as well as the process of DNA methylation.
Increased exposure to endogenous and exogenous oestrogen has been described as a risk factor for cancer in several hormone-dependent tissues such as the breast, endometrium, ovary, uterus, and prostate. If the COMT enzyme is dysfunctional, this might lead to the decreased inactivation of oestrogen and a build-up of damaging oxidative products.
Strategies to minimize risk for increased oestrogen exposure may thus be of value. Risk factors include obesity (obesity increases endogenous oestrogen production by fat tissue, where the enzyme aromatase converts androgens into oestrogen); high serum insulin (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); alcohol consumption (reportedly increases oestrogen levels); use of oral contraceptives or oestrogen replacement therapy (moderate alcohol use may be synergistically enhanced when combined with HRT); exposure to environmental toxins found in pesticides, herbicides, plastics, refrigerants, industrial solvents (that are structurally similar to oestrogen and have the ability to mimic harmful oestrogens in the body) as well as the hormones used to fatten livestock and promote milk production (found in inorganic meat and milk products).
Dietary considerations to optimise oestrogen balance:
- Include insoluble dietary fibre such as lignin (found in flaxseeds and the bran layer of grains, beans, and seeds) as it 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 SHBG levels, thus increasing levels of free oestrogen.
- Antioxidant nutrients can reduce the oxidation of oestrogen catechols and promote greater excretion of these metabolites through the methylation pathway. These include vitamins E and C, α-lipoic acid, N-acetylcysteine, selenium, curcumin, and green tea.
- Curcumin, a polyphenol complex from the curry spice turmeric (which is a member of the ginger family), also increases components important in the Phase II detoxification of quinones produced from the oxidation of catechol oestrogens.
- Calcium D-Glucarate increases the activity of the glucuronidation Phase II pathway, with the net effect of increased oestrogen and toxin elimination from the body.
Impact of Catechol-O-Methyltransferase Val158Met (rs4680) Polymorphism on Breast Cancer Susceptibility in Asian Population
Rai et al, 2017.