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Genetic polymorphisms and women's health.


A single nucleotide polymorphism (SNP) is a common genetic change seen in people. A SNP represents a difference in a single DNA building block, which is called a nucleotide. It is a substitution of one base for another. SNPs occur throughout a person's DNA, and these variations are found in the DNA between genes. (1) When SNPs occur within a gene or in an area near a gene, they may play a role in the development of disease by affecting the gene's function. Researchers have found SNPs that predict an individual's response to certain drugs, susceptibility to environmental toxins, and risk of developing diseases. (1) SNPs are different than genetic mutations in DNA that cause disease. Disease-causing mutations occur within a gene's coding or regulatory regions. Disease-causing mutations affect the function of the protein encoded by the gene. SNPs are not necessarily located within genes, and they may not always affect the way a protein functions, but they correspond to the risk for getting a certain disease. (2) Some SNPs, however, do affect protein function correlating with a disease. They may change the amino acid sequence of the gene's protein product or change the timing, location, or level of gene expression. (2) There are numerous SNPs located throughout the body. Several occur in estrogen metabolism genes that are linked to increased risk for estrogen-driven conditions in women. This discussion of the link between single nucleotide polymorphisms and women's health conditions will focus on the liver biotransformation pathways and the MTHFR gene. There are of course many more SNPs that affect estrogen metabolism and many other conditions linked to SNPs than what are discussed here. This is merely an introduction to the link between SNPs in genes and women's health conditions.

The Liver

Some SNPs affect the liver's biotransformation pathways in humans. The liver is important in protecting us from potentially toxic chemical exposures. This protective ability stems from the expression of enzymes whose function is to catalyze the oxidation, reduction, and hydrolysis reactions (phase I metabolism) and/or conjugation reactions (phase II metabolism) of functional groups on drug and chemical molecules. One of the major enzyme systems that determines the liver's ability to deal with drugs and chemicals is the cytochrome P450 enzymes. These enzymes are located in several places in the body but predominately in the liver. They are responsible for phase I biotransformation or metabolism. Other enzyme systems include dehydrogenases, oxidases, esterases, reductases, and a number of conjugating enzyme systems including glucuronosyltransferases, sulfotransferases, and glutathione S-transferases. These are responsible for phase II liver biotransformation. (3) There are over 50 human genes coding for the various phase I cytochrome P450 (CYP) enzymes. There are several CYP isoforms that are of particular importance due to their involvement in metabolism of drugs, hormones, and other exogenous substances including environmental toxicants. These include CYP1A1, CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP2E1, CYP2E6, CYP2D6, CYP2C9, CYP2C19, and CYP2C8. Phase II conjugation reactions include glucuronidation, glutathione transferases, S-methylation, N-methylation, acetylation, sulfotransferases, thioltransferases, and glycination (amino acid conjugation). (4) Any of these may be polymorphic, affecting liver phase I and II biotransformation pathways.

Polymorphisms of cytochrome P450 enzymes were first described about 30 years ago when a small proportion of people given the antihypertensive drug debrisoquine had extreme falls in blood pressure which were related to abnormally high plasma drug concentrations. (5) It has since been found that debrisoquine and well over 70 other drugs are metabolized by the enzyme known as CYP2D6 in the liver. CYP2D6 metabolizes numerous medications. Population studies have shown that approximately 8% of Caucasians but less than 1% of Asians have a SNP of 2D6 and are poor metabolizers. As for phase II liver biotransformation pathways, the first polymorphism was described over 40 years ago for acetylation. It is now known that N-acetyltransferase (NAT) Is controlled by two genes (NATI and NAT2), of which NAT2 A and B are responsible for clinically significant metabolic polymorphisms. (5) SNPs of liver phase I and phase II biotransformation pathways affect more than just drug metabolism. They are responsible for metabolizing environmental chemicals and hormones such as estrogen. SNPs can be linked to disease especially related to women's hormonal health.

Women's Health

Many women's health conditions have been linked to specific SNPs of cytochrome P450 enzymes and conjugation reactions as well as MTHFR gene function. Several laboratories are now offering tests that look for these genetic variations that may either explain a patient's health condition or determine her risk for developing disease. Polymorphisms occur in several areas of the body, not just the liver. As a simple introduction to correlating SNPs to disease, the link between four common women's health conditions and a few estrogen-metabolizing gene polymorphisms is described. This is by no means a complete review.


Endometriosis is a common disease, causing menstrual pain and infertility. It is a multifactorial condition with links to estrogen metabolism and environmental toxicants. Studies correlating the role of polymorphisms are mixed, with newer studies starting to make connections. The glutathione S-transferases (GSTs) are a family of enzymes responsible for the metabolism of xenobiotics and carcinogens in phase II liver biotransformation. GSTM1, one member of the GST family, is important in the detoxification of the toxicants and oxidative stress product during ovulation. GSTM1 gene polymorphism is associated with endometriosis. A significant excess of the GSTM null genotype (gene deletion) is also seen among women with endometriosis. (6) The GSTM1 null genotype is related to an increased susceptibility to endometriosis. The GSTM1 gene polymorphism likely contributes to the pathogenesis of endometriosis.

Endometriosis is an estrogen-dependent condition that can be influenced by defective signaling in the estrogen pathway. Estrogen metabolizing polymorphisms can be associated with defective hormonal signaling, leading to disease. A recent study linked polymorphism of CYP19A1 to endometriosis. (7) CYP19A1 is found in the endoplasmic reticulum and catalyzes the last steps of estrogen biosynthesis. Mutations in this gene can result In either increased or decreased aromatase activity. A 2014 study looked at 500 women with endometriosis and 500 women without the condition and found CYP2C19 associated with endometriosis. (8) Some studies report conflicting information on the link between SNPs and endometriosis. An older 2001 study showed no link to GSTM1 null genotype alone but did find a link to endometrioses if a woman had both GSTM1 null and a CYP1A1 polymorphism. (9) CYP1A1 is another phase I cytochrome P450 enzyme responsible for estrogen metabolism.


Polycystic ovary syndrome (PCOS) is a very common condition affecting thousands of women. It's a leading cause of infertility and a complex multifactorial disorder involving a number of genetic and environmental factors. CYP1A1 encodes a phase I cytochrome P450 enzyme involved in the oxidative metabolism of estrogens. Emerging evidence suggests that common functional polymorphisms in the CYP1A1 gene increase susceptibility to PCOS, but individually published results are inconclusive. However, a recent meta-analysis published in 2013 looked at five case-control studies with a total of 1036 subjects, including 521 PCOS cases and 515 healthy controls. The meta-analysis indicates that the CYP1A1 polymorphism may contribute to increasing susceptibility to PCOS among the general female population in Turkey and India. (10)

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have recently been linked to several health conditions. It has also become common for practitioners to test patients for MTHFR polymorphisms. The MTHFR gene provides instructions for making the methylenetetrahydrofolate reductase enzyme, which plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the vitamin folate. A 2015 study set out to determine if there is an association of C677T and A1298C polymorphisms of MTHFR gene with the susceptibility to PCOS. Blood samples of 115 PCOS patients and 58 fertile non-PCOS women were collected for DNA extraction. The results show that the MTHFR gene C677T polymorphism is associated with PCOS. The A1298C polymorphism of the MTHFR gene is not associated with the occurrence of PCOS. Also, the study determined the folate level in red blood cells is lower in PCOS patients, for whom folate should be supplemented. (11)


Uterine leiomyomas (fibroids) are a common estrogen-dependent condition. It has been suspected that SNPs in genes involved in estrogen metabolism might play a role in the development of fibroids. Liver phase I enzymes CYP1A1 and CYP1B1, along with phase II COMT and GST pathways, are mostly responsible for estrogen metabolism in the liver. The results of a 2015 meta-analysis suggest that CYP1A1 polymorphism is significantly associated with uterine leiomyoma risk. (12) In 2014 a group of researchers evaluated all the estrogen metabolism enzyme gene polymorphisms and risk of developing fibroids. The genetic polymorphisms in COMT, CYP1A1, and Alall9Ser loci in CYP1B1 were risk factors for uterine leiomyoma development. However, Leucine432Valine locus in CYB1B1 may be a protective factor. (13)

This is an important distinction to note when testing patients for SNPs. Many labs simply report that the COMT or CYP1B1 is positive for a SNP but don't report where on the gene loci. This study broke down CYP1B1 and tested several gene loci and found that one was a risk factor for developing fibroids and another was protective. A 2015 study also found Leuclne4B2Valine SNP In the gene encoding cytochrome CYP1B1 possibly protective against the formation of uterine fibroids. (14)

The COMT liver phase II biotransformation pathway is not the only phase II pathway linked to the formation of uterine fibroids. The GST gene polymorphisms play a role as well. Although less often studied, It appears that there is a link to uterine fibroids and GSTT1 null polymorphism In the Iranian population. The null genotype significantly Increased the susceptibility to uterine leiomyoma compared with Individuals carrying the present genotype. (15)

Breast Cancer

This is the area with perhaps the most research linking estrogen-metabolizing gene polymorphisms and an estrogen-dependent condition. The CYP3A4 is a major enzyme catalyzing the metabolism of both endogenous and exogenous agents that may play a role In the development of cancer. It Is responsible for metabolizing hormones and the majority of pharmaceutical medication. Studies show a link between CYP3A4 polymorphism and an increased risk for breast cancer as well as taxane toxicity In breast cancer patients undergoing chemotherapy using taxanes. (16,17) A recent meta-analysis Indicated that the GSTM1 and GSTP1 polymorphisms might significantly contribute to breast cancer susceptibility In Asian populations, especially East Aslan. (18)

Genetic polymorphisms of CYP1B1 and 1A1 are also associated with breast cancer In Caucasian women. (19,20) An Interesting study published in Environmental Health linked SNPs of CYP1A1, CYP17, and COMT and levels of serum perfluorooctane sulfonate (PFOS) and periluorooctanolc acid (PFOA) to Increased risk of breast cancer. (21) These are known estrogen-disrupting chemicals and used In the manufacturing of Gore-Tex and Teflon products, and they contaminate drinking water.

The MTHFR enzyme is essential for DNA synthesis and DNA methylation, and Its gene polymorphisms have been linked to several health conditions as previously mentioned. Several studies have Investigated the association between the MTHFR polymorphism and breast cancer risk, but the results have been Inconclusive. However, 2014 meta-analysis of 22 case-control studies found that MTHFR C677T polymorphism was significantly associated with breast cancer risk in the Chinese population. Meanwhile, MTHFR A1298C polymorphism was not associated with breast cancer risk in the Chinese population. (22) More research in this area is currently under way.


Single nucleotide polymorphisms (SNPs), a common genetic change seen In people, were first described over 40 years ago in relation to Impairment In drug metabolism. More recently, links have been made between SNPs and the development of disease. Both patients and practitioners are testing for SNP gene polymorphisms In an attempt to explain a current health condition or determine the risk for developing a disease. Gene polymorphisms occur throughout the body, and several SNPs of estrogen metabolism and the link to women's health conditions were described here. Many studies are conflicting in the area of SNPs' correlating to disease, but there Is enough research making a positive association to find the Information useful. Clearly more research needs to be done In the area, including valid methods to assist the functioning of gene polymorphism as a means to prevent diseases linked to that SNP.


(1.) What are single nucleotide polymorphisms? [Web page]. Genetics Home Reference. Sept 16, 2013. Accessed Nov 9, 2015.

(2.) Making SNPs make sense [Web page]. Genetic Science Learning Center. June 22,2014. http://learn. Accessed Nov. 9, 2015.

(3.) Meyer UA. Overview of enzymes of drug metabolism. J Pharmacokinet Biopharm. 1996;24(5):449-59.

(4.) Lord RS, Bralley JA. Laboratory Evaluations for Integrative and Functional Medicine. 2nd ed. Duluth, GA: Metametrix Institute; 2008.

(5.) Shenfield GM. Genetic polymorphisms, drug metabolism and drug concentrations. Clin Biochem Rev. 2004;25(4):203-206.

(6.) Yao-Yuan Hsieh et al. Glutathione S-transferase M1*null genotype but not myeloperoxidase promoter G-463A polymorphism is associated with higher susceptibility to endometriosis. Mol Hum Reprod. 2004;10(10):713-717.

(7.) Trabert B et al. Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil Steril. 2011;96(6):1401-1406.

(8.) Christofolini DM et al. CYP2C19 polymorphism increases the risk of endometriosis. J Assist Repro Genet. 2014;32(1):1-5.

(9.) Hadfield RM et al. Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1. Mol Hum Reprod. 2001 Nov;7(11):1073-1078.

(10.) Shen W et al. CYP1A1 gene polymorphisms and polycystic ovary syndrome risk: a meta-analysis and meta-regression. Genet Test Mol Biomarkers. 2013;17(10):727-735.

(11.) Qi Q et al. Association of methylenetetrahydrofolate reductase gene polymorphisms with polycystic ovary syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015;32(3):400-404.

(12.) Wang F et al. CYP1A1 genetic polymorphisms and uterine leiomyoma risk: a meta-analysis. Int J Clin Exp Med. 2015 Mar 15;8(3):3590-3594.

(13.) Shen Y et al. Role of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in Han Chinese: a case-control study. J Obstet Gynaecol Res. 2014 Apr;40(4):1077-1084.

(14.) Bideau VS, Alleyne AT. Leu/Val SNP polymorphism of CYP1B1 and risk of uterine leiomyoma in a Black population. Tumour Biol. Epub 2015 Oct 20.

(15.) Dehraisi MSS et al. P0165 GSTT1 null polymorphisms and susceptibility to uterine leiomyoma in an Iranian population. Eur J Cancer. 2014;50(4):e56

(16.) Figueroa, JD, Brinton LA. Unraveling Genes, hormones, and breast cancer. J Natl Cancer Inst. 2012;104(9):641-642.

(17.) Boso V et al. SNPs and taxane toxicity in breast cancer patients. Pharmacogenomics. 2014;15(15):1845-1858.

(18.) Tang J et al. Association of glutathione S-transferase T1, M1 and P1 polymorphisms in the breast cancer risk: a meta-analysis in Asian population. Int J Clin Exp Med. 2015;8(8):12430-12447.

(19.) Liu JY et al. Association between the CYP1B1 polymorphisms and risk of cancer: a meta-analysis. Mol Genet Genomics. 2015;290(2):739-765.

(20.) Hefler LA et al. Estrogen-metabolizing gene polymorphisms in the assessment of breast carcinoma risk and fibroadenoma risk in Caucasian women. Cancer. 2004;101(2):264-269.

(21.) Ghisari M et al. Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case-control study in Inuit women. Environ Health. 2014;13(1):19.

(22.) Liang H et al. Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies. Tumour Biol. 2014 Feb;35(2):1695-1701.

by Marianne Marchese, ND

Dr. Marchese is the author of 8 Weeks to Women's Wellness. She received her doctorate in naturopathic medicine from the National College of Naturopathic Medicine in 2002. Dr. Marchese maintains a private practice in Phoenix, Arizona, and teaches gynecology at Southwest College of Naturopathic Medicine. She was named in Phoenix Magazine's Top Doctor Issue as one of the top naturopathic physicians in Phoenix. Dr. Marchese lectures on topics related to women's health and environmental medicine throughout the US and Canada,
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Title Annotation:Environmental Medicine Update
Author:Marchese, Marianne
Publication:Townsend Letter
Article Type:Report
Date:Feb 1, 2016
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