Genomics: Insight

Research Question

We hypothesize that genome-wide association studies (GWAS) can be a valuable tool to create screening for detecting the presence of genes linked to endometriosis risk variants, allowing women to access a more efficient diagnosis that could lead to better treatments.

If improved, the GWAS could be a crucial asset to help bridge the gap that we currently see in women's health, where marginalized groups receive dismissal of symptoms, wrong diagnoses, or no diagnoses.1 Moreover, these groups, when diagnosed with endometriosis, present higher risks within surgical procedures, as women of color undergo the highest rates of hysterectomies and open abdominal laparoscopic surgeries for endometriosis treatment.¹

Endometriosis

Endometriosis is a chronic inflammatory disease that is caused by the presence of endometrial tissue outside of the uterus.² Surgical procedures to treat endometriosis include hysterectomies and open abdominal laparoscopic surgeries.¹ Endometriosis etiology is often debated as it is an idiopathic condition, but two possible theories for endometriosis diagnosis are genetic factors and the retrograde menstruation phenomena.³ Retrograde menstruation is when the menstrual blood will flow backward into the pelvic space as compared to exiting the vaginal cavity.² Symptoms of endometriosis may include chronic issues of pain in the pelvic area, hemorrhages, and infertility issues.¹ Genome-wide association studies (GWAS) are genetic methods that scan the genome of many people to identify genetic markers associated with a disease. GWAS have been crucial in

identifying genetic variants through providing biomarkers that are associated with endometriosis which lead to early detection of the condition.⁴

Women’s Health, Population, & Disparities 

Women’s health includes emotional, social, cultural, and physical well-being.5 This broad specialty dives into various conditions and treatments that are unique, prevalent, or more serious in women. More than 176 million women are diagnosed with endometriosis worldwide, affecting about 5-10% of the reproductive population.⁶ Despite the disease's high prevalence, it does not consider that the diagnosis may come with a 4 to 11-year delay.⁷ Some probable factors that influence the disparities for endometriosis would be a misdiagnosis, lack of patients' confidence in providers, and race.^6–8 Minority groups show the highest rates of misdiagnosis for endometriosis and complications in surgical procedures when diagnosed.¹ Disparities in race and socioeconomic status show that wealthy, and white women have the lowest rates of invasive procedures as they opt for minimally invasive hysterectomies.¹

The study conducted by Alexander et al. identifies several factors that could contribute to the higher rates of open abdominal hysterectomies among Black women, among these are the socioeconomic status, insurance coverage and healthcare provided bias that does not provide patient with a full range of options, options available to white women.9

Women of color have been shown to have the highest incidences of mortality and complications surrounding operations for endometriosis.¹ Likewise, women of color have been found to have the highest rates of invasive surgeries like open abdominal laparoscopies as compared to white women who mainly undergo minimally invasive hysterectomies.¹ As a consequence, we see major complications, including cardiopulmonary arrest, sepsis, and renal failure.¹ These disparities in

complications persist even after a study adjusted for variables such as age, body mass index, and comorbidities, suggesting that factors like access to care and systemic biases may contribute.⁹

Women of color, along with having larger margins of error and risk associated with surgeries, have had longer hospital stays and higher rates of readmittance as compared to white women.¹ Historically, endometriosis research has focused on the condition present in white women utilizing this group as the sample, often leading to misdiagnosis in other racial groups.¹⁰ The disparities within race have provided unsatisfactory care and higher-risk procedures revolving around endometriosis.

Diagnosis and Treatments 

The basic diagnosis of endometriosis is done through ultrasound.¹¹ Additional methods such as transvaginal ultrasound and magnetic resonance imaging can be used to help with diagnosis, but need to be qualified as a replacement.¹² A more invasive procedure is laparoscopy, which is considered the gold standard for endometriosis diagnosis.¹³ It involves surgery to insert the laparoscope into the pelvis for visualization of lesions alongside histological confirmation.¹¹

While more reliable, surgery can be risky and expensive, and an accurate, low-invasive test would reduce the need for laparoscopy.¹²

Current treatment and management of endometriosis involves pharmacological and surgical intervention. The goal of pharmacological intervention is to suppress ovulation and estrogen production.14 In hormone therapy, there are drugs that reduce estrogen levels through the reduction of gonadotropin-releasing hormone (GnRH) or inhibit enzymes in estrogen production.^11,15 Another focus is pain management, which can also be achieved through various drugs.¹¹ Surgical intervention depends on the severity of the endometriosis. It is utilized if drug therapies have failed, pelvic pain, and/or endometrial ovarian cysts.11,16 Side effects can accompany such surgeries, such as premature menopause, when the removal of the ovaries is needed.¹⁶

The current methods of identifying endometriosis are laparoscopies and open abdominal laparoscopies (laparotomies) create a higher risk of complications. GWAS can lessen the risks present during surgical procedures as well as in identifying the condition through genes involved in the disease, possibly leading to specialized treatments for patients with endometriosis. However, with current GWAS focusing only on those of European, Japanese, and Taiwanese-Han descent, new studies including other groups will need to be conducted.

Genome Studies

Three genetic loci reported to be associated with endometriosis risk shared across European, Japanese, and Taiwanese-Han descent are WNT4, CDC42, and CCDC170.^17-19 WNT4 and CDC42 are located on 1p36.12. WNT4 is important for the development of the female reproductive organs.²⁰ CDC42 acts as a molecular switch and is implicated in signaling cascades to initiate cellular process change.²¹ It has been reported that genetic variations in WNT4 and CDC42 contribute to endometriosis risk and have a role in endometriosis development.^21,22 CCDC170 is located on 6q25.1. It is involved in the sex hormone pathway and has evidence of being an endometriosis risk locus.¹⁹ These three loci may be better focused for general screening for endometriosis risk across people of European or East Asian descent. To our knowledge, there is currently no GWAS of endometriosis, including other women of color, that can be used to further identify common risk loci. The lack of GWAS may stem from the historical view of endometriosis as a condition of white women, shifting focus of the research to that particular group.¹⁰ The underrepresentation of women of color in studies and medical education in general may also have an influence.¹⁰

There are more loci associated with endometriosis risk but they are different across populations. In GWAS of European and Japanese descent, loci reported to have association with endometriosis risk include VEZT, GREB1, and those in the sex hormone pathway (FN1, ESR1, STNE1, and FSHB).19,23 The GWAS focused on women of Taiwanese-Han descent and identified two new significant loci, C5orf66/C5orf66-AS2, and STN1.¹⁷ Endometriosis risk seems to be further influenced by different loci found in populations with differing descent.

Our research highlighted the need for more GWAS that focuses on different population cohorts to create a database that is accessible and can be used for every patient independently of their race.

Potential Use of Identified Gene Loci

GWAS can be used to identify populations at risk of endometriosis. Screening patients for certain loci associated with risk variants can help with the early detection of endometriosis. A genetic risk prediction using data from GWAS may help determine those with a genetic predisposition. However, to make application feasible, a better understanding of risk loci that contribute to endometriosis is required. More studies into other populations may help identify common risk loci found across most, if not all, women. GWAS can potentially create a new screening process that is less invasive than current ones. Early diagnosis and intervention can result in a better prognosis.

Loci identified in certain pathways related to endometriosis can be used to create new specialized treatments. There are currently targeted therapeutic approaches being developed through an understanding of the genetic basis of endometriosis, including anti-angiogenic therapy, immunotherapy, and hormonal therapy.⁴ Furthermore, development for non-invasive diagnostics by detecting genetic alterations is underway.⁴

Conclusion

Genome-wide association studies (GWAS) can be useful for risk prediction and suggesting the potential involvement of genetic loci in disease pathophysiology, providing more precise and earlier diagnoses of endometriosis. Endometriosis being a condition of unknown cause, along with the need for invasive procedures for diagnosis, can create late and imprecise diagnoses. The current methods of identifying endometriosis are laparoscopies and open abdominal laparoscopies (laparotomies) create a higher risk of complications. Ultrasound can be a non-invasive and cost-effective way to detect endometriosis, but cannot detect all types of endometriosis.²⁴ GWAS can lessen the risks present during surgical procedures as well as in identifying the risk of developing

endometriosis condition through genes involved in the disease, possibly leading to specialized treatments for patients with endometriosis. Earlier detection using GWAS may provide more options for the patient, especially if fertility is a concern. The earlier endometriosis is treated, the more likely the patient will not require in vitro fertilization.¹⁶ Complete removal of the uterus and/or ovaries will not have to be an option. Earlier treatment can prevent end-organ damage and bowel obstructions, which may require surgery as treatment at that stage.¹⁶ However, with current GWAS focusing only on those of European, Japanese, and Taiwanese-Han descent, new studies including other groups will need to be conducted.

References

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