A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin.

BACKGROUND

Severe hypercholesterolemia (HC, LDL-C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL-C.

METHODS

Summary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used.

RESULTS

A 36-SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL-C trait and explained 8% of its variability (p = 10 ). After risk categorization, the risk of having HC was higher in the high- versus low-risk group (RR = 4.17, p < 1 × 10 ). Compared to a 12-SNP LDL-C raising score (currently used in the United Kingdom), the PRS explained more LDL-C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL-C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL-C raising score were reclassified to intermediate or high risk by the new PRS.

CONCLUSION

The new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms.