A multicenter study led by researchers at Vanderbilt University Medical Center has identified multiple new genes associated with benign tumors (fibroids) of the uterus, the leading indication for hysterectomy in the country.
Their report, published in the journal Nature Communications, is another step toward development of targeted therapies aimed at reducing the incidence and medical burden of this common condition, which costs the U.S. health care system billions of dollars annually.
“These results from the largest, most ancestrally heterogeneous population evaluated to date provide us with better leverage to discover new treatments for fibroids and improve the lives of millions of women,” said Todd Edwards, PhD, MS, associate professor of Medicine in the Division of Epidemiology.
“Our results move us closer to being able to use genetic information to identify those at risk of fibroids before they suffer from symptoms and present clinically, and predict who will respond to different therapies,” added Jacklyn Hellwege, PhD, research assistant professor of Medicine in the Division of Genetic Medicine.
Edwards and Hellwege co-led the study with Digna Velez Edwards, PhD, MS, professor of Obstetrics and Gynecology, director of the Center for Women’s Health Research, and holder of the Lucius E. Burch Chair of Reproductive Physiology and Family Planning.
More than 70% of women in the United States will develop fibroids by the age of 50. Those with symptomatic fibroids experience heavy and abnormal menstrual bleeding and pelvic pain.
Established risk factors include and are not limited to early menarche (age of the first period), family history, obesity, hypertension, vitamin D deficiency and stressful life events.
Previous genome-wide association studies (GWAS), which detect correlations between genetic variations and disease, have identified 72 fibroid-associated genes.
The current study undertook a large, multiancestral GWAS meta-analysis of genomic variation in DNA samples donated by more than 74,000 women with uterine fibroids and by more than 465,000 controls who did not have fibroids.
Several biorepositories, including VUMC’s BioVU, were involved in this portion of the study, which identified 11 previously unpublished, fibroid-associated genes.
The researchers also used S-PrediXcan, a technique for predicting how changes in gene expression may contribute to various health conditions. They then used a statistical method called colocalization to filter those results to the subset of genes most likely to represent causal relationships between genetic variants and fibroid risk.
Applying these methods, they discovered an additional 46 novel fibroid-associated genes. These genes were significantly enriched in (commonly a part of) signaling networks that play a role in the development of cancer, cellular growth and proliferation, cell death and survival, and diseases of the reproductive system.
In particular, the researchers found an association between fibroids and an increased predicted expression in uterine tissue of HEATR3, a gene previously linked to cell proliferation, metastasis and bladder cancer. “Further research into the role of increased HEATR3 gene expression in fibroid pathogenesis may illuminate future therapeutic directions,” they concluded.
The study, which was supported by several grants from the National Institutes of Health, “is the dividend from 15 years of NIH-funded fibroids genetics research at VUMC, as well as institutional investments in the BioVU biobank,” Edwards noted.
Jeewoo Kim, a graduate student in Human Genetics at VUMC, is the paper’s first author. Other co-authors from VUMC are Elizabeth Jasper, PhD, Sarah Jones, MPH, James Jaworski, MPH, Megan Shuey, PhD, and Wei-Qi Wei, MD, PhD. The research was supported in part by NIH grants UL1TR000445, K12AR084232, R01HD074711, R03HD078567, R01HD093671 and R01HD112169.
