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Study Examines Impact of Reporting Secondary Findings

NEW YORK (GenomeWeb) – In an attempt to assess the impact of reporting secondary findings from genetic tests, researchers from Brigham and Women's Hospital reported this week the results of a study that analyzed whether patients who were tested for APOE genotype status because of a family history of Alzheimer's disease were negatively impacted if they were also told of their risk of cardiovascular disease.

The group, which included members of the Risk Evaluation and Education for Alzheimer's Disease study group, reported their results this week in the Annals of Internal Medicine.

In the study, the researchers analyzed the APOE status of 257 participants, some of whom were randomized to receive results related to Alzheimer's risk and others to receive both Alzheimer's risk and coronary artery disease risk results. The participants were then followed for one year to see how receiving results impacted measures of anxiety and depression as well as lifestyle and health changes.

"We found that telling individuals who wanted to learn about their risk for Alzheimer's disease about their risk for both Alzheimer's disease and coronary artery disease actually reduced distress among some people, and motivated many to make improvements to their lifestyle," Kurt Christensen, lead author of the study and a researcher at Brigham and Women's Hospital, said in a statement.

Previous studies have found that individuals want the choice of receiving secondary findings, and most have said that they want such findings, especially when they are actionable. However, other studies have found that when individuals have to be proactive in obtaining those results, they rarely do.

Groups, particularly those that are part of the Clinical Sequencing Exploratory Research consortium, are now studying the impact of returning such findings.

In this most recent study, the researchers analyzed just one gene, rather than an entire exome or genome, and evaluated the impact of also receiving information on a secondary finding.

The researchers enrolled 257 asymptomatic adults both older and younger than 60 years, 69 percent of whom had one first-degree relative affected by Alzheimer's.

The team analyzed the APOE genotype of all participants in the study, identifying 83 who had the APOE E4 genotype, which is associated with an increased risk for developing Alzheimer's, and 174 non-carriers.

Of those who had the E4 genotype, 32 were counseled on both Alzheimer's risk and coronary artery disease risk, while 51 were counseled only about Alzheimer's disease risk.  

Among the noncarriers, half were counseled only about Alzheimer's and half were counseled about Alzheimer's and coronary artery disease.

The researchers found that among carriers of E4, individuals who were counseled about both diseases had less anxiety than those counseled solely about Alzheimer's risk one-year later and had slightly less distress six months and immediately after receiving results. There were no differences between the groups who were not carriers. As expected, individuals who were positive for the E4 genotype had higher levels of anxiety and distress than those without it.

Interestingly, the researchers found that individuals counseled about the impact of the APOE E4 genotype on coronary artery disease were more likely to make behavioral and lifestyle changes than those counseled only about Alzheimer's. The changes, however, were modest and did not lead to significant differences in aerobic activity, flexibility, or strength.

In addition, around 33 percent of individuals counseled for both diseases shared their results with a physician compared to 22 percent in the Alzheimer's-only counseling group.

"This research is reassuring, and provides evidence that secondary genomic findings disclosure can have a substantial positive psychological and behavioral impact on patients," Robert Green, principal investigator of the study and medical geneticist at Brigham and Women's, said in a statement.

However, the authors acknowledged that the nature of the disease for which they reported secondary findings could impact individuals' reactions to the results. For diseases like coronary artery disease, there are concrete actions individuals can take to reduce their risk, such as exercising more or changing their diet. The researchers noted that they did not evaluate the reverse situation — individuals who's primary reason for testing was to find out their risk for coronary artery disease, but finding a risk for Alzheimer's was incidental. The impact may have been different in this situation, since there are no treatments available for Alzheimer's.

In addition, there are many knowledge gaps regarding the impact of disease-associated variants. For instance, in the case of APOE E4 and its relationship to coronary artery disease, the authors noted that other researchers have questioned the relationship and wrote that "meta-analyses published during our study suggest that increased [coronary artery disease] risk among APOE E4 carriers may be modest."

Other groups have also identified similar challenges in returning other potentially disease-causing variants found incidentally. For instance, researchers from the University of Washington found significant differences among laboratories in whether or not they classify the same secondary finding as pathogenic. The group also noted that population data on differences between prevalence and penetrance was lacking.

Similarly, a group from Vanderbilt University Medical Center published a study in JAMA earlier this month finding differences in whether laboratories classified variants in two genes associated with cardiac arrhythmias as pathogenic or not when evaluating asymptomatic individuals.