Additive value of polygenic risk and family history for coronary heart disease risk stratification in two diverse US cohorts

Area of Science:

• Cardiovascular Disease Epidemiology
• Genetics and Genomics
• Preventive Cardiology

Background:

• Coronary heart disease (CHD) risk prediction models often lack comprehensive integration of genetic and familial factors.
• The additive value of polygenic risk scores (PRS_CHD), familial hypercholesterolemia (FH) variants, and family history (FamHx) for CHD risk across diverse populations remains under-evaluated.

Purpose of the Study:

• To assess the independent and additive contributions of PRS_CHD, FH variants, and FamHx to CHD risk prediction.
• To evaluate the incremental predictive value of these factors when added to existing clinical risk algorithms (PCEs) across different self-identified race/ethnicity (SIRE) groups.

Main Methods:

• Utilized two large, diverse US cohorts (eMERGE phase IV and All of Us) including over 250,000 participants.
• Quantified associations using multivariable logistic regression and Cox proportional hazards models.
• Assessed predictive performance via c-statistic, reclassification, and decision-curve analysis at actionable 10-year risk thresholds.

Main Results:

• PRS_CHD and FamHx demonstrated independent and additive associations with CHD risk.
• These associations were consistent across White, Black, and Latino SIRE groups.
• Incorporating PRS_CHD and FamHx into PCEs significantly improved CHD prediction (increased c-statistic) and reclassified a notable proportion of participants, particularly at 7.5% 10-year risk thresholds.

Conclusions:

• Polygenic risk scores and family history are independently and additively associated with CHD across major US racial/ethnic groups.
• These findings support the integration of PRS_CHD and FamHx into clinical risk prediction tools for enhanced CHD identification.
• The study highlights the potential for improved preventive strategies by incorporating genetic and familial risk information.