Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial)

Abstract

Background: Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels.

Methods and results: Participants (n=203, 45-65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ((+)GRS). Participants in the (+)GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or (+)GRS (n=103). At the end of the study period, the (+)GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P=0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not participants with low GRS (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the (+)GRS group than in the CRS group (39% versus 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted.

Conclusions: Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936675.

Keywords: coronary disease; genetic risk disclosure; genetic risk score; genomics; hydroxymethylglutaryl-CoA reductase inhibitors; polymorphism, single-nucleotide; prevention & control; randomized clinical trials.

Figure 1

Flow diagram of the MI-GENES Clinical Trial. Of the 2026 individuals from the Mayo Biobank who met the eligibility criteria, a random subset of 1000 was genotyped. Genotyping results passed quality control measures in 968 individuals. Recruitment was based on screening genotyping results in order to achieve the targeted enrollment goals of ~110 individuals with high GRS (≥1.1) and ~110 with average/low GRS (<1.1) with the expectation that approximately 10–20 study participants may withdraw from the study or be lost to follow-up. Participants who withdrew from the study stated that they could not fit the study visits into their schedule. (ASCVD: atherosclerotic cardiovascular disease; CHD: coronary heart disease; GRS: genetic risk score).

Figure 2

Change in LDL-C levels from baseline over the follow up period overall and in categories of GRS. LDL-C levels at 6 months post-disclosure were lower in ⁺GRS participants than CRS participants. The overall downward longitudinal trend in LDL-C was significantly greater in ⁺GRS participants than CRS participants. LDL-C levels at 6 months post-disclosure were lower in ⁺H-GRS participants than CRS participants. The downward trend in LDL-C was significantly greater in ⁺H-GRS participants than CRS participants. There was a trend towards a greater reduction in LDL-C levels in ⁺H-GRS vs. ⁺L-GRS. *denotes six month statistical significance at 0.05 level.

Figure 3

Dietary fat intake, physical activity and anxiety levels in the study groups. There was no difference between CRS and ⁺GRS group in either dietary fat intake, physical activity, or anxiety levels 6 months post-disclosure. Dietary fat intake scores ranged between 0 (no fat intake) to 110 indicative of very high dietary fat intake. Physical activity scores ranged between 7 (active) and 1 (sedentary). Anxiety scores ranged between 20 (least anxious) up to 80 (highly anxious).