Framingham Heart Study: One woman’s genomic journey

Just over a year ago, Susan Martin – not her real name – a retiree in her 60s from Boston, received a phone call just as she was about to settle into an episode of the West Wing. She wanted to ignore the call, but the name on the phone’s identifier – Framingham Heart Study (FHS) – made her think twice.

Martin knew a lot about FHS, an NHLBI-funded study that for 76 years has been looking for common factors and family patterns in cardiovascular disease. Martin herself was a participant, just as her parents had been and her grandparents before that. So she answered the call, and on the other end was Jodi Hoffman, M.D., a clinical geneticist at Boston Medical Center, who told her she had some news to share – but only if Martin wanted to hear it.

Martin said yes and braced herself.

Hoffman explained that one of the study’s tests showed that Martin had a possible genetic variant that could affect her heart, but that the result needed to be confirmed through a saliva test. Did she want to go through with it to find out more?

A frenzy of thoughts ran through Martin’s head. “But I really perked up when I was told there was a 50% possibility that my three younger siblings and my two kids had a chance of inheriting this variant, too,” Martin said.

That was the beginning of an eye-opening, months-long journey for Martin. And she’s hardly alone. Because of remarkable advances in genomic science – the study of all of a person’s genes – people around the world are getting the chance to learn if something in their genome has gone awry, and what it might mean for their health in the future.

The genome’s hidden secrets

That’s because the genome holds a host of clues to our health and well-being. With the advent of more cost-effective genome sequencing and better tools to analyze the data, scientists can now follow where those clues lead, and they’re making discoveries. They now have a better understanding of what genes do – not only when they are functioning normally, but also when mutations arise and sometimes cause the gene to go haywire, leading to disease.

The American College of Medical Genetics and Genomics (ACMG) keeps a running list of genetic variants that are known to have an adverse effect on health. So far there are 81 so-called medically actionable genes that ACMG recommends for returning clinical results because there are measures that could be taken to prevent or treat individuals who carry the genetic variation. The most well-known of these genes are the BRCA genes, which have been implicated in hereditary breast and ovarian cancers.  Having a genetic variation in one of these genes does not necessarily mean a person will get a disease but identifying the medically actionable variations is important, experts say, because if a person has one, prevention measures, such as lifestyle changes, and specific treatment options, like medications or surgery, may be available that could extend or save their life.

The goal of FHS was never to go searching for these genetic variants initially, but rather to identify the common factors or characteristics that contribute to cardiovascular disease, said Yuling Hong, M.D., M.Sc., Ph.D., chief of the epidemiology branch in NHLBI’s Division of Cardiovascular Sciences and program officer for the FHS. The researchers do that by collecting different types of data, such as blood pressure recordings, cholesterol readings, and genomic information from blood. When they discover something in the genome that might lead to disease, such as breast cancer or specific heredity forms of cardiovascular diseases, they feel they have an ethical obligation to give study participants the option to learn that information.

“In many ways, FHS is different from other cohort studies,” Hong said. Having decades of family histories to refer to and compare makes the data especially rich for researchers, he noted. “The first generation of the study was in 1948 and now they are on the third. The study participants are passionate about the research because of this history.”

One set of Martin’s own grandparents, who lived in Framingham, Mass., were part of the first generation FHS cohort, and her parents joined as part of the second generation. Because her father had congestive heart failure and experienced two heart attacks at an early age, Martin knew her own family’s story could be valuable, so when she was asked to sign up, she didn’t hesitate. “I felt it was my responsibility to join,” she said. “The researchers make it so easy and are so grateful for your participation. I have nothing but respect for the experience.”

Every five to seven years participants get new medical assessments and exams, but one change has been notable. “When I first joined, I remember signing all sorts of forms that said if there was a life-threatening result discovered, the researchers would report it to me. But generally, I did not find out results from my personal assessments.”

FHS started returning genetic results from older sequencing technologies 12 years ago and added next-generation sequencing results seven years ago. Study participants have the option, with consent, to learn about medically actionable genetic information if they choose. Martin had signed that release.

A personal choice

A few weeks after that unsettling phone call, Martin completed the saliva test and confirmed that she does indeed have a mutation in a gene called MYBPC3, which tells the cells in the heart how to make a protein involved in heart muscle contractions. Having this gene variant can lead to greater risk of developing conditions related to the structure of the heart.

Martin scheduled a follow-up call with Hoffman, who answered her questions and told her what to expect next – an EKG and a referral to a cardiologist who would follow her yearly for the rest of her life. Hoffman also highly recommended Martin share that she had this genetic variant with her primary care physician, her children, and her siblings.

As Martin quickly found out, choosing to know you might have a variant in your genome that could be harmful to your health is a very personal decision. All three of her siblings had different responses to that possibility and chose their own paths. Martin was understanding, as she knew there was much to consider.

Some of the genetic conditions uncovered might not have a cure, though Hong says that certain treatment options or lifestyle changes could slow the progress of a disease. “Even with no cure presently, it still may be helpful to know that you could potentially reduce your risk or take charge of your health,” he said. Having this information a person could work together with their medical team to address long-term care.

Living her best life

Today, Martin is living much of the way she did before the phone call. She’s still an avid runner who plays pickleball five times per week and walks her dog regularly. But now, she said, if she finds herself having shortness of breath or being excessively tired, she won’t ignore it and will get checked out by her cardiologist.

In this way, Martin said, the newfound information has been helpful, and she’s “extremely pleased” she was given the choice to learn about it. From the start, the researchers gave her every opportunity to hear only as much information as she could manage. “I was very grateful for that,” she said. “It confirmed what I felt about FHS – that they are taking our best interests to heart, even though their main goal is research.”

“It’s been an honor and a privilege to be a part of the experience.”