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Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults.

Publication ,  Journal Article
Khan, SS; Page, C; Wojdyla, DM; Schwartz, YY; Greenland, P; Pencina, MJ
Published in: Circulation
August 23, 2022

BACKGROUND: Understanding the predictive utility of previously derived polygenic risk scores (PRSs) for long-term risk of coronary heart disease (CHD) and its additive value beyond traditional risk factors can inform prevention strategies. METHODS: Data from adults 20 to 59 years of age who were free of CHD from the FOS (Framingham Offspring Study) and the ARIC (Atherosclerosis Risk in Communities) study were analyzed. Because the PRS was derived from samples of predominantly European ancestry, individuals who self-reported White race were included. The sample was stratified by age and cohort: young (FOS, 20-39 years [median, 30 years] of age), early midlife (FOS, 40-59 years [median, 43] years of age), and late midlife (ARIC, 45-59 years [median, 52 years] of age). Two previously derived and validated prediction tools were applied: (1) a 30-year traditional risk factor score and (2) a genome-wide PRS comprising >6 million genetic variants. Hazard ratios for the association between each risk estimate and incident CHD were calculated. Predicted and observed rates of CHD were compared to assess discrimination for each model individually and together with the optimism-corrected C index (95% CI). RESULTS: Among 9757 participants, both the traditional risk factor score (hazard ratio per 1 SD, 2.60 [95% CI, 2.08-3.27], 2.09 [95% CI, 1.83-2.40], and 2.11 [95% CI, 1.96-2.28]) and the PRS (hazard ratio, 1.98 [95% CI, 1.70-2.30], 1.64 [95% CI, 1.47-1.84], and 1.22 [95% CI, 1.15-1.30]) were significantly associated with incident CHD in young, early midlife, and late midlife, respectively. Discrimination was similar or better for the traditional risk factor score (C index, 0.74 [95% CI, 0.70-0.78], 0.70 [95% CI, 0.67-0.72], and 0.72 [95% CI, 0.70-0.73]) compared with an age- and sex-adjusted PRS (0.73 [95% CI, 0.69-0.78], 0.66 [95% CI, 0.62-0.69], and 0.66 [95% CI, 0.64-0.67]) in young, early-midlife, and late-midlife participants, respectively. The ΔC index when PRS was added to the traditional risk factor score was 0.03 (95% CI, 0.001-0.05), 0.02 (95% CI, -0.002 to 0.037), and 0.002 (95% CI, -0.002 to 0.006) in young, early-midlife, and late-midlife participants, respectively. CONCLUSIONS: Despite a statistically significant association between PRS and 30-year risk of CHD, the C statistic improved only marginally with the addition of PRS to the traditional risk factor model among young adults and did not improve among midlife adults. PRS, an immutable factor that cannot be directly intervened on, has minimal clinical utility for long-term CHD prediction when added to a traditional risk factor model.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

August 23, 2022

Volume

146

Issue

8

Start / End Page

587 / 596

Location

United States

Related Subject Headings

  • Young Adult
  • Risk Factors
  • Risk Assessment
  • Proportional Hazards Models
  • Middle Aged
  • Humans
  • Genetic Predisposition to Disease
  • Coronary Disease
  • Cardiovascular System & Hematology
  • 4207 Sports science and exercise
 

Citation

APA
Chicago
ICMJE
MLA
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Khan, S. S., Page, C., Wojdyla, D. M., Schwartz, Y. Y., Greenland, P., & Pencina, M. J. (2022). Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults. Circulation, 146(8), 587–596. https://doi.org/10.1161/CIRCULATIONAHA.121.058426
Khan, Sadiya S., Courtney Page, Daniel M. Wojdyla, Yosef Y. Schwartz, Philip Greenland, and Michael J. Pencina. “Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults.Circulation 146, no. 8 (August 23, 2022): 587–96. https://doi.org/10.1161/CIRCULATIONAHA.121.058426.
Khan SS, Page C, Wojdyla DM, Schwartz YY, Greenland P, Pencina MJ. Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults. Circulation. 2022 Aug 23;146(8):587–96.
Khan, Sadiya S., et al. “Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults.Circulation, vol. 146, no. 8, Aug. 2022, pp. 587–96. Pubmed, doi:10.1161/CIRCULATIONAHA.121.058426.
Khan SS, Page C, Wojdyla DM, Schwartz YY, Greenland P, Pencina MJ. Predictive Utility of a Validated Polygenic Risk Score for Long-Term Risk of Coronary Heart Disease in Young and Middle-Aged Adults. Circulation. 2022 Aug 23;146(8):587–596.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

August 23, 2022

Volume

146

Issue

8

Start / End Page

587 / 596

Location

United States

Related Subject Headings

  • Young Adult
  • Risk Factors
  • Risk Assessment
  • Proportional Hazards Models
  • Middle Aged
  • Humans
  • Genetic Predisposition to Disease
  • Coronary Disease
  • Cardiovascular System & Hematology
  • 4207 Sports science and exercise