Impact of Genetic Variations in Endometriosis

Should Genetics Be Considered the Pre-eminent Etiologic Factor in Endometriosis?

Key Points

Highlight:

• Dr. Giudice group from the University of California summarizes the impacts of genetic variation, recent discoveries of genetic risk factors and the role of genomic studies in endometriosis.

Background:

• The understanding of endometriosis remains a major clinical challenge.
• Endometriosis has a complicated etiology, influenced by genetic and environmental factors.
• Recently, more than 40 genetic risk factors have been discovered in endometriosis.
• A significant amount of somatic mutation has been found, expanding the possible functions of DNA variation in the pathogenesis of endometriosis.

Key points:

• Genetic variation and disease risk
  • The most common variation between individuals is referred to as single-nucleotide polymorphisms (SNPs).
  • SNPs located in the regulatory sequence in the DNA responsible for the function of the protein, have more subtle effects.
  • The combination of altered regulation by these SNPs predisposes to many common diseases.
  • Genome-wide association studies (GWASs) advances the mapping of genetic risk factors for endometriosis.
• Heritability
  • Australian twin's study showed that the rates of endometriosis in identical twin sisters are much higher than the non-identical twin.
  • The estimated genetic contribution to risk, or heritability, of endometriosis, is about 0.51.
• Genetic Risk Factors for Endometriosis
  • Genomic signals associated with the estrogen receptor 1 gene (ESR1), upstream of follicle-stimulating hormone (FSH), and estrogen-regulated and early response gene (GREB1) are highly implicated in endometriosis.
  • International mapping efforts are continuing with numerous collaborative projects.
  • However, few data sets included in large studies with surgically confirmed and detailed clinical data is the major current limitation.
• Somatic Mutations
  • Somatic mutations are alterations in DNA not inherited from parents.
  • In 24 patients with deep infiltrating endometriosis lesions, a somatic mutation was found in 79%.
  • These results demonstrated that endometriosis is more likely that a single endometrial epithelial progenitor cell undergoes expansion to form glandular tissue at the site of the lesion.
  • Numerous pieces of evidence strongly support the important role of somatic mutation in endometriosis development and progression.

Lay Summary

Endometriosis is an estrogen-dependent disorder. This disease affects approximately 7% to 10% of reproductive-aged women and causes negative impacts on society. The underlying causes are unclear; therefore, the understanding of this disease remains a major clinical challenge. Endometriosis has a complicated etiology, influenced by genetic and environmental factors. Thanks to the current advances in genetics, more than 40 genetic risk factors have been discovered in endometriosis. Also, a significant amount of somatic mutation has been found, expanding the possible functions of DNA variation in the pathogenesis of endometriosis.

In this review, Dr. Giudice group from the University of California summarizes the impacts of genetic variation, recent discoveries of genetic risk factors and the role of genomic studies in endometriosis. This paper was recently published in “The Journal of Minimally Invasive Gynecology”.

Genetic variation and disease risk: A broad spectrum of genetic variants has been contributing to human diseases. Especially endometriosis is influenced by a large number of variants, each with small effects. The most common variation between individuals is referred to as single-nucleotide polymorphisms (SNPs). SNPs are only different at a single base position in the DNA and many of them have no functional consequence. However, SNPs located in the regulatory sequence in the DNA responsible for the function of the protein, have more subtle effects. The combination of altered regulation by these SNPs predisposes to many common diseases. Genome-wide association studies (GWASs) advances the mapping of genetic risk factors for endometriosis. 

Heritability: The increased abundances of endometriosis among the relatives of women with endometriosis than in the control demonstrated the genetic effects on endometriosis. According to the studies of Australian twins, the rates of endometriosis in identical twin sisters are much higher than the non-identical twin. And the estimated the genetic contribution to risk, or heritability, of endometriosis, is about 0.51. A similar result was found in Sweden's twin study.

Genetic Risk Factors for Endometriosis: Endometriosis is an estrogen-dependent disease. Therefore, genomic signals associated with estrogen receptor 1 gene (ESR1), upstream of follicle-stimulating hormone (FSH), and estrogen-regulated and early response gene (GREB1) are highly implicated in endometriosis. International mapping efforts are continuing with numerous collaborative projects. However, few data sets included in large studies with surgically confirmed and detailed clinical data is the major current limitation.

Somatic Mutations: Somatic mutations are alterations in DNA not inherited from parents. In 24 patients with deep infiltrating endometriosis lesions, a somatic mutation was found in 79%. These results demonstrated that endometriosis is more likely that a single endometrial epithelial progenitor cell undergoes expansion to form glandular tissue at the site of the lesion, not originated from a single stem or progenitor cells. Numerous pieces of evidence strongly support the important role of somatic mutation in both endometriosis development and progression.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/31683028