Bridging the Genomic Equity Gap with Context-Enhanced Risk Stratification in American Indians: the Strong Heart Study

Area of Science:

• Genomics
• Cardiovascular Epidemiology
• Precision Medicine

Background:

• Polygenic scores (PGS) are valuable for disease risk stratification but often lack portability across diverse populations.
• American Indians experience high cardiovascular disease (CVD) burden but are underrepresented in genomic studies, hindering equitable precision medicine.
• Limited portability of PGS across ancestries restricts their clinical utility, particularly for underrepresented groups.

Purpose of the Study:

• To assess if integrating lifestyle and clinical context variables with PGS improves cardiometabolic risk prediction in European and American Indian cohorts.
• To evaluate the impact of gene-context interactions on risk prediction models for blood pressure, coronary heart disease (CHD), and stroke.

Main Methods:

• Compared genetics-only models with full models including context variables and gene-context interactions.
• Utilized data from 424,622 European participants (UK Biobank) and 3,157 American Indian participants (Strong Heart Study).
• Assessed prediction accuracy and model discrimination for cardiometabolic traits.

Main Results:

• Integrating context variables significantly improved prediction accuracy for cardiometabolic traits in both European and American Indian cohorts.
• The enhanced model incorporating context and genetic interactions showed significantly improved discrimination for CHD in American Indians compared to existing clinical models.
• Gene-context interactions played a crucial role in refining risk prediction, particularly for underrepresented populations.

Conclusions:

• Modeling the interplay between genetic predisposition and modifiable factors (lifestyle, clinical context) can mitigate the loss of predictive power from imperfect PGS transferability.
• This integrated approach offers a promising strategy for developing more equitable and effective precision medicine tools for underrepresented populations.
• Enhancing PGS portability through context variable integration is vital for advancing health equity in cardiovascular disease prevention.