About 17 percent of women with unexplained infertility also have gene variants known to cause diseases, from common conditions like heart disease to rare problems like ALS, Medical College of Georgia researchers report.
Theirs appears to be the first study to identify an increased prevalence of disease-causing genetic variants in women with unexplained infertility, reports the team, led by Lawrence C. Layman, MD, in New England Journal of Medicine.
They hypothesized that genetic disease predisposes to infertility and subsequent medical illness, and their findings support this connection, they write. Women with infertility, for example, have been noted to have an increased risk of cardiovascular disease.
“The disease link was known, but what wasn’t known was whether there was a genetic link. That was the purpose of this study,” says Layman, a reproductive endocrinologist and geneticist who heads the MCG Section of Reproductive Endocrinology. , Infertility and Genetics at Augusta University
The researchers note that although clear, common pathways between infertility and conditions such as heart disease have yet to be established, “a strong association between infertility and future disease may still aid early detection, genetic counseling, and intervention.” ». Fertility could actually be a ‘biomarker’ for future medical illness, they write.
They sequenced the exomes, which contain the protein-coding regions of genes, of 197 females aged 18 to 40 with unexplained infertility, a figure that includes about 30% of infertile females, to look for variants in genes known or suspected to cause them. disease.
Information on the women was drawn from the National Institute of Child Health and Human Development Eunice Kennedy Shriver Cooperative Reproductive Medicine Network’s AMIGOS Trial, a cohort of about 900 couples from multiple institutions without an obvious cause of infertility, such as ovulation problems or unhealthy sperm.
They found that 6.6% of the females they studied had variants in 59 genes that are called “medically active,” meaning they are likely to cause conditions such as heart disease and breast cancer, but there are interventions, lifestyle and/or medical actions which may remove or at least reduce their risk. In comparison, about 2.5% of the general population has been found to have variants in these genes.
An additional 10% of females had gene variants known to cause diseases for which little or no action could be taken to improve the problem, such as Parkinson’s disease, Layman says.
They found 14 medically active gene variants in 13 of the females. one woman had two variants. The most common were those that contribute to cardiovascular disease and cancer, the nation’s two leading killers.
These included relatively well-known variants, such as four women with BRCA1 and BRCA2 variants, which are associated with a high risk of breast or ovarian cancer. Six women had variants in five genes associated with increased risk of cardiovascular disease, including a genetic predisposition to high cholesterol levels and irregular heart rhythms, some of which can be fatal.
One woman had a variant of the MYH11 gene, which is associated with an increased risk of rupture of the aorta, the largest blood vessel in the body. Numerous rare variants of uncertain significance were also found in medically active genes.
Comparably large datasets that better represent the entire population, such as 50,000 individuals in the UK Biobank and nearly 22,000 in the National Human Genome Research Institute-funded eMERGE network, yielded rates of 2 and 2.5%, respectively.
This translates to about a threefold increase in medically active gene variants among women who were infertile compared to the general population, Layman says.
In addition, they found 20 variants in 21 other women in genes associated with conditions that likely could not be moderated, such as a dramatically increased risk of developing the muscle-wasting ALS or Lou Gehrig’s disease and kidney-destroying polycystic kidney disease that will eventually require dialysis and/or kidney transplantation, a finding that requires more study, Layman and colleagues write.
All told, 17% of females with unexplained infertility had variants known to cause or suspected of causing future medical disease. They note that their findings are likely to relate only to this group of women.
While more study is needed before making moves like recommending genetic testing for all women or men with unexplained infertility, the researchers say their findings support the idea that the higher incidence of future medical problems in these women may have a genetic component.
At present, genetic testing in infertility is done selectively, such as if the suspected problem suggests a genetic cause, such as a male with no sperm, which may indicate Klinefelter syndrome, where men are born with an extra copy of the X chromosome that it results from a random genetic error.
“We don’t do genetic testing right now because there’s no good evidence for it and it’s not going to be covered by insurance,” Layman says. Their new study provides more evidence that genetic testing may need to be considered in a few years down the line if the findings continue to hold.
“We need to study a lot more people, and other people need to do it as well,” Layman says.
Another area that needs further investigation is whether some of the gene variants may be causes of both infertility and disease, Layman says. Right now, the only variants known to him that appear to play a role in both are the BRCA 1 and 2 carcinogens, because they are also involved in meiosis, which is important for the formation and function of sperm and eggs. They’re also both involved in repairing double-strand breaks in DNA, which has been linked to ovarian aging and cancer risk, Layman says.
Another is a variant that causes early menopause, which is known to increase the risk of heart disease because estrogen is thought to be protective of the female cardiovascular system.
He hopes the new findings will inspire others to further investigate whether the disease-causing variants they found in these women are also factors in their infertility.
Layman also notes that the database they studied happened to be largely white women, but that infertility is a problem common to both blacks and whites as well as other races, and should be studied in those populations. .
Infertility also affects men and women equally, according to the American Society for Reproductive Medicine.
One of Layman’s many pursuits includes a larger study that also includes men. He wants to do genetic studies on couples and then continue to follow them beyond the point of seeking reproductive assistance to assess specifically when and if diseases associated with the genetic variants they found start to appear.
While Layman has some patients he follows long-term, most of his patients come to him during the years they are working to have a child, and some of the conditions, such as breast cancer, that can result from gene variants they found tend to occur a decade or more later. He has wondered what happened to his patients’ lives in the long term because of the associations that have been made between infertility and a handful of diseases.
When the National Institutes of Health issued a funding opportunity in 2020 for research exploring infertility as a marker for overall health in light of growing evidence that “fertility status may be a window into overall health,” she decided to further explore the associations .
Dr. Michael Diamond, a reproductive endocrinologist who is senior vice president for research at AU, is a longtime principal investigator at the National Institute of Reproductive Medicine Cooperative for Child Health and Human Development. Diamond made it possible for the university to join the partnership, designed to enable large clinical trials that improve the diagnosis and treatment of reproductive health problems, a decade ago when he came to MCG and AU from Wayne State University in Detroit. Diamond is a co-author on the new study at NEJM.
Dr. Michael P. Dougherty, who completed his reproductive endocrinology fellowship with Layman and is now in practice in New Jersey, is the first author.
Today, 72 genes are considered medically applicable by the American College of Medical Genetics and Genomics.