Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized, Controlled Trial.

Christensen KD, Roberts JS, Whitehouse PJ, Royal CD, Obisesan TO, Cupples LA, Vernarelli JA, Bhatt DL, Linnenbringer E, Butson MB, Fasaye GA, Uhlmann WR, Hiraki S, Wang N, Cook-Deegan R, Green RC; REVEAL Study Group.

Abstract

BACKGROUND:

Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information.

OBJECTIVE:

To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD).

DESIGN:

Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917).

SETTING:

Four teaching hospitals.

PARTICIPANTS:

257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative.

INTERVENTION:

Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only).

MEASUREMENTS:

Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months.

RESULTS:

At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, -1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, -1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ± 5 points. Among carriers of the APOE ϵ4 allele, distress was lower in the AD+CAD groups (difference, -4.8 [CI, -8.6 to -1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype.

LIMITATIONS:

Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants.

CONCLUSION:

Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk.