The genetic predisposition to endometriosis

Genetic factors play a role in the etiopathogenesis of endometriosis, although candidate genes are not exactly identified.

Key Points

Highlights:

• Although the mechanism underlying endometriosis is not clearly understood, the occurrence of multifactorial interactions including genetic and immunological factors are widely accepted.

Importance:

• Understanding the genetic causes that play a role in the pathogenesis of endometriosis through recent technological advances will enable early diagnosis and treatment of the disease.

What’s done here?

• This review summarizes studies investigating the underlying genetic causes of endometriosis.
• All published literature including review, observational, cohort, and case-control studies published between 1980 and 2018 have been evaluated through an online search of the MEDLINE database and a manual search of relevant publications.

Key results:

• The first study of endometriosis genetic predisposition was published in 1980 by Simpson et al.; evaluated 123 women with endometriosis, found 6.9% of first-degree relatives were affected compared to the control group.
• Hadfield demonstrated in twin studies that endometriosis in twins was diagnosed with the same severity. Treolar et al. showed that the concordance ratio 2:1 between monozygotic and dizygotic twins, and the genetic risk ratio 2.34 for endometriosis of sisters.
• The candidate genes playing role in endometriosis etiopathogenesis relate to the molecular alterations of steroidogenesis, sex hormone receptor activity, inflammation, immune response, tissue remodeling, neoangiogenesis, metabolism regulation, and DNA reparation.
• The polymorphism dysregulating estrogen and progesterone receptor-ligand signaling and altered tissue sensitivity to progesterone have been shown to result in altered hormonal equilibria and promote estrogenic activity.
• Cytokine polymorphisms include transforming growth factor beta 1 (TGFβ1) and tumor necrosis factor alpha (TNFα) showed that inflammatory response alterations are present in the endometriosis pathogenesis.
• Semino et al. showed that ectopic endometriotic cells express more class I major histocompatibility complex (MHC) molecules (HLA system), preventing their natural killer (NK)-mediated death facilitating survival resulting in endometriosis.
• In terms of neoangiogenesis and tissue remodeling, other pathogenetic mechanisms; Vascular endothelial growth factor (VEGF) and endothelial growth factor receptor (EGFR) are involved in neoangiogenesis regulation, tissue remodeling, cell proliferation.
• The association between the development of endometriosis and oxidative stress has been explained with the genetic polymorphism in DNA reparation.
• On the other hand, “hypothesis-free” approach including analysis of family linkage, genome-wide association studies (GWASs) and next-generation sequencing (NGS), without pre-selecting a particular gene or region without an initial pathogenic hypothesis.
• Family linkage studies aim to detect rare variant genes in resulting in the familial aggregation of a specific disease showed a strong linkage with chromosome regions 10q26 and 20p1330. 
• GWASs define common genetic variants in the general population associated with the disease risk. The first GWAS (2010) and second by International Endogene Consortium (IEC) in 2011 identified a significant association with (SNP)s especially in stage III-IV endometriosis.
• However, the specific genes associated with endometriosis have not yet been identified using GWAS.    

Lay Summary

Endometriosis is an estrogen-dependent gynecological disease mostly encountered in reproductive-aged women. Although endometrium is a non-malignant disease, its symptoms can range from mild to severe due to the inflammation that ectopic endometrial tissue forms around itself.

The exact etiopathogenetic mechanism has not been understood, although several mechanisms support the presence of a genetic predisposition. A group of scientists from Italy and Greece, led by Dr. Angioni, recently published a review entitled “Genetics of endometriosis: a comprehensive review” in the journal named as Gynecological Endocrinology.

The authors aimed to review the association between endometriosis and genetics by evaluating all the review, observational, cohort, and case-control studies published from 1980 to 2018. Due to recent technological improvements, the genetic association with endometriosis could be better understood although there are some inconsistent and contradictory results between the studies. Some candidate genes have been identified playing a role in the etiopathogenesis of endometriosis. however, it is not possible to determine a specific genetic risk in endometriosis yet.  

The first study supporting the genetic predisposition of endometriosis was published in 1980 by Simpson, which evaluated 123 women with histologically confirmed endometriosis and found 6.9% of first-degree relatives were affected compared with the control group. Twin studies revealed that endometriosis in twins occurs with the same severity.  

Genetic analyses clarified that endometriosis etiopathogenesis relates to the molecular alterations of steroidogenesis, sex hormone receptor activity, inflammation, immune response, tissue remodeling, neoangiogenesis, metabolism regulation, and DNA repair. Estrogen and progesterone receptor-ligand signaling dysregulation resulting in altered tissue sensitivity to progesterone is caused by an altered hormonal equilibrium to promote estrogenic activity. Inflammatory response alterations such as cytokine polymorphisms include transforming growth factor beta 1 (TGFβ1) and tumor necrosis factor alpha (TNFα) are also present in the endometriosis pathogenesis. Ectopic endometriotic cells expressing more class I major histocompatibility complex (MHC) molecules (HLA system), prevent their natural killer (NK)-mediated death facilitating survival of endometriosis. The factors related to neoangiogenesis and tissue remodeling (VEGF, EGFR) involved in endometriosis pathogenesis.

“Rapid technological advancements in genetics can open doors to meaningful developments in the future, in terms of understanding the molecular mechanisms of pathogenesis, the development, and maintenance of endometriosis, and determining the search key for a new therapeutic target in this highly debilitating disease,” they added.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/30909768