Polygenic Risk Score for Low-Density Lipoprotein Cholesterol Is Associated With Risk of Ischemic Heart Disease and Enriches for Individuals With Familial Hypercholesterolemia

Author:

Wu Haoyu12ORCID,Forgetta Vincenzo2ORCID,Zhou Sirui12,Bhatnagar Sahir R.13ORCID,Paré Guillaume4567ORCID,Richards J. Brent1238ORCID

Affiliation:

1. Department of Epidemiology, Biostatistics, and Occupational Health (H.W., S.Z., S.R.B., J.B.R.), Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada.

2. Center for Clinical Epidemiology (H.W., V.F., S.Z., J.B.R.), Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada.

3. Department of Diagnostic Radiology (S.R.B.) and Department of Human Genetics (J.B.R.), McGill University, Montréal, QC, Canada.

4. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences, ON, Canada (G.P.).

5. Departments of Pathology and Molecular Medicine (G.P.), McMaster University, Hamilton, ON, Canada.

6. Departments of Epidemiology and Biostatistics (G.P.), McMaster University, Hamilton, ON, Canada.

7. Department of Biochemistry (G.P.), McMaster University, Hamilton, ON, Canada.

8. Department of Twin Research, King’s College London, United Kingdom (J.B.R.).

Abstract

Background: The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). Methods: We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease among 3010 cases and 38 738 controls. Results: Among the 41 748 whole-exome sequenced White British individuals, 1-SD increase in the LDL-C PRS was associated with elevated LDL-C among both FH variant carriers (0.34 [95% CI, 0.22–0.47] mmol/L) and noncarriers (0.42 [95% CI, 0.42–0.43] mmol/L). Among individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (odds ratio, 2.20 [95% CI, 1.66–2.71] per SD). Each SD increase in the LDL-C PRS was associated with risk of ischemic heart disease to the comparable magnitude as measured LDL-C (odds ratio, 1.24 [95% CI, 1.20–1.29] and odds ratio, 1.15 [95% CI, 1.09–1.23], respectively). The LDL-C PRS was not strongly associated with other traditional ischemic heart disease risk factors. Conclusions: An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between ischemic heart disease and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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