BACKGROUND: Endometriosis has a strong genetic component, and numerous genetic studies have been reported. METHODS: We have systematically reviewed these studies and included 114 in our final selection. RESULTS: We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case–control studies. CONCLUSIONS: The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis.

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Functional genetic polymorphisms and female reproductive disorders: Part II—endometriosis

Endometriosis is a benign gynecological disease with an unclear pathophysiology characterized by ectopic endometrium causing endometrium-like inflammatory lesions outside the uterine cavity. Recently, a number of studies have investigated genetic polymorphisms as a possible factor contributing to th

Endometriosis and genetic polymorphisms.

We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case–control study aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels on BC risk in Greenlandic Inuit women. The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572); CYP19A1 (C> T; rs10046) and CYP19A1 ((TTTA)n repeats) polymorphisms and BRCA1 founder mutation using TaqMan allelic discrimination method and polymerase chain reaction based restriction fragment length polymorphism. The χ2 –test was used to compare categorical variables between cases and controls and the odds ratios were estimated by unconditional logistic regression models. We found an independent association of CYP1A1 (Val) and CYP17 (A1) with BC risk. Furthermore, an increased BC risk was observed for women with high serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and carriers of at least: one CYP1A1 variant Val allele; one variant COMT Met allele; or the common CYP17 A1 allele. No combined effects were seen between PFAS exposure and CYP1B1 and CYP19 polymorphisms. The risk of BC was not found significantly associated with exposure to PCBs and OCPs, regardless of genotype for all investigated SNPs. The frequency of the Greenlandic founder mutation in BRCA1 was as expected higher in cases than in controls. The BRCA1 founder mutation and polymorphisms in CYP1A1 (Val) and CYP17 (A1) can increase the BC risk among Inuit women and the risk increases with higher serum levels of PFOS and PFOA. Serum PFAS levels were a consistent risk factor of BC, but inter-individual polymorphic differences might cause variations in sensitivity to the PFAS/POP exposure.

/pdf/polymorphisms-in-phase-i-and-phase-ii-genes-and-breast-1mo31zfalu.pdf

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

Family and twin studies have shown that heritability accounts for endometriosis development to an extent similar to other complex genetic diseases. Both linkage analysis and association studies have been performed to identify genetic determinants for the disease. Results from the linkage scan of 1,176 families collected thanks to a joint effort between an Australian and a UK group supported significant linkage to a novel susceptibility locus on chromosome 10q26. Although gene variants with effects on the disease predisposition have been proposed to exist and several candidates have been put forward, their effects have not been or are yet to be confirmed. The main categories of candidate genes studied have been those involved in detoxification processes, sex steroid biosynthesis and action, immune system regulation. Genetic studies on endometriosis face numerous challenges as the disease has several manifestations and different forms. Moreover, strong gene-environmental interactions might definitively influence approaches to identify genetic variants involved. Genome-wide association studies that survey most of the genome for causal genetic variants provide the potential for future progress.

Genetics of endometriosis: Current status and prospects

Endometriosis is a sex steroids-dependent disease. It has been postulated that certain genetic polymorphisms involved in sex steroids biosynthesis and metabolisms may be associated with increased risk of developing endometriosis. Despite a deluge of reports of positive associations of endometriosis with numerous polymorphisms involving sex steroids production and metabolism, the results are often conflicting. We performed a meta-analysis of 12 association studies on 5 genes (CYP17, CYP19, AR, PR and ER). We found that many reported positive findings were not supported by the data due to faulty analysis. There have been no functional data that support a putative relationship of these genetic polymorphisms with endometriosis. A handful of positive findings so far have not been independently replicated, and should be viewed as preliminary. In addition, these findings should be counterbalanced by legitimate concerns of multiple comparisons, small prior probability of association with a particular polymorphism, proper selection of controls, and lack of replication (at least until now). In future association studies, it may be productive to put more thought to study design, execution, and data analysis.

Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a meta-analysis.

Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17α, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T→C) in the 5′-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III–IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III–IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in t...

Norita Ohara

Papers

Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations