Disproportionate percentage of women with unexplained infertility have gene variants known to cause heart problems and cancer

About 17% of women with unexplained infertility also have gene variants known to cause disease, from common conditions like heart disease to rare problems like ALS, Medical College of Georgia researchers report.

Their research appears to be the first study to identify an increased prevalence of disease-causing genetic variants in women with unexplained infertility, the team, led by Lawrence C. Layman, MD, reports in the New England Journal of Medicine.

They hypothesized that genetic diseases create a predisposition to infertility and subsequent medical illness, and their findings support that link, they write. For example, women with infertility have been found to have an increased risk of cardiovascular disease.

“The connection to disease is known, but what wasn’t known was whether there was a genetic connection. That was the goal of this study,” said Layman, a reproductive endocrinologist and geneticist who heads the MCG section of Reproductive Endocrinology. , Infertility and Genetics at Augusta University

The researchers note that while clear, common pathways between infertility and conditions such as heart disease have still not been established, “a strong association between infertility and future disease may still aid early detection, genetic counseling and intervention.” In fact, fertility could be a “biomarker” for future medical conditions, they write.

They sequenced the exomes, which contain the protein-coding regions of genes, from 197 females aged 18 to 40 with unexplained infertility, a percentage that comprises about 30% of infertile females, to look for variants in genes that were known or suspected became that they cause disease.

Information on the women was drawn from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network’s AMIGOS Trial, a group of some 900 couples from multiple institutions with no clear cause for infertility, such as problems with ovulation or unhealthy food. semen.

They found that 6.6% of the females they studied had variants in 59 genes that are termed “medically useful,” meaning they are likely to cause conditions such as heart disease and breast cancer, but there are interventions, lifestyle and/or medical, that remove them or at least reduce their risk. In comparison, about 2.5% of the general population are found to have variants in these genes.

Another 10% of the females had gene variants known to cause diseases for which little to no action could be taken to correct the problem, such as Parkinson’s disease, Layman says.

They found 14 variants of the medically useful genes in 13 of the females; a woman had two variants. The most common were those contributing to cardiovascular disease and cancer, the country’s two leading causes of death.

These were relatively well-known variants, such as four women with variants of BRCA1 and BRCA2, which are associated with a high risk of breast or ovarian cancer. Six females had variants in five genes linked to the increased risk of cardiovascular disease, things like a genetic predisposition to high cholesterol and irregular heart rhythms, some of which can be fatal.

One woman had a variant in the MYH11 gene, which is associated with an increased risk of rupturing the aorta, the largest blood vessel in the body. Numerous rare variants of uncertain significance were also found in the medically useful genes.

Relatively large datasets that better represent the entire population, such as 50,000 people in the UK Biobank and nearly 22,000 in the National Human Genome Research Institute-funded eMERGE network, yielded percentages of 2 and 2.5%, respectively.

That translates to about a threefold increase in variants in medically useful genes among the females that were infertile compared to the general population, Layman says.

In addition, they found 20 variants in 21 other females in genes associated with conditions that are unlikely to be alleviated, such as a dramatically increased risk of developing muscle-wasting ALS, or Lou Gehrig’s disease, and kidney-defeating polycystic kidney disease, which will eventually require dialysis and/or a kidney transplant, a finding that requires more research, Layman and colleagues write.

All told, about 17% of women with unexplained infertility had variants known or suspected to cause future medical illness. They note that their findings are likely relevant only to this group of women.

While more research is needed before steps are taken, such as 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. to have.

At present, genetic testing in infertility is done selectively, for example if the suspected problem points to a genetic cause, such as a man without sperm, which may indicate Klinefelter syndrome, in which men are born with an extra copy of the X chromosome that 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 covered by insurance,” says Layman. Their new study provides more evidence that genetic testing may need to be considered a few years later if the findings persist.

“We need to study a lot more people and other people need to do the same,” says Layman.

Another area that needs further investigation is whether some of the gene variants could be the cause of both infertility and disease, Layman says. At the moment, the only variants known to him that appear to play a role in both are carcinogenic BRCA 1 and 2, as they are also involved in meiosis, which is important for sperm and egg cell formation and function. They’re also both involved in repairing double-strand breaks in DNA, which has been linked to ovarian aging and cancer risk, says Layman.

Another is a variant that causes early menopause, which is known to increase the risk of heart disease because estrogen is considered 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 females 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 blacks and whites and other races, and should be studied in these 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 includes men. He wants to do genetic studies on couples and then monitor them until they seek reproductive help to specifically assess when and if diseases associated with the genetic variants they’ve found surface.

While Layman has a number of patients that he follows on a long-term basis, most of his patients come to him during the years when they are working to have a child, while some of the conditions, such as breast cancer, that can result from the gene variants those they found tend to occur a decade or more later. He has questioned what has happened in the long-term lives of his patients because of associations that have been made between infertility and a handful of illnesses.

When the National Institutes of Health released a funding opportunity in 2020 for research on infertility as a marker of overall health in the face of mounting evidence that “fertility status can be a window into overall health,” he 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 of the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network. Diamond enabled the university to join the cooperative, designed to facilitate 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 of the new study in the NEJM.

Dr. Michael P. Dougherty, who completed his reproductive endocrinology fellowship at Layman and is now based in New Jersey, is the lead author.

Today, 72 genes are considered medically useful by the American College of Medical Genetics and Genomics.

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