A Father's Last Message: The Value of Polygenic Risk Scoring in Familial CAD

Abstract

Background/Synopsis

Given the strong familial aggregation of CAD, genetic profiling has the potential to enhance CVD risk assessment. Historically, this approach has been limited to the identification of monogenic variants, which fail to explain most of the heritable CVD risk in the population. Genome wide association studies have identified numerous single nucleotide variants (SNVs) associated with CVD risk. Polygenic risk scoring (PRS) provides a quantitative assessment of CVD risk based on the number of identified SNVs and their respective effect sizes. PRS has been shown to significantly improve event prediction when used in conjunction with the AHA/ACC risk calculator.

Objective/Purpose

Here, we describe a family with a significant burden of premature CVD who demonstrate strong correlation between PRS and their clinical phenotypes.

Methods

Case presentation: AA is a 24-year-old female with newly diagnosed CAD s/p 2 vessel CABG and hypercholesterolemia with no pathogenic variants associated with monogenic familial hypercholesterolemia. She presented to lipid clinic for new evaluation one week before her wedding. She was found to have combined hyperlipidemia and lipoprotein(a)>2x upper limit of normal (ULN). Within five days, her 54-year-old father (DD) experienced acute myocardial infarction/sudden cardiac death (AMI/SCD). AA's 55-year-old mother, BB, was subsequently found to have combined hyperlipidemia as well, and after a period of grieving and stabilization, underwent cardiac evaluation demonstrating obstructive triple-vessel CAD requiring 2x percutaneous coronary intervention (PCI) with drug-eluting stents (DES). BB has combined hyperlipidemia and Lp(a)>2x ULN. AA's younger sister, CC, age 22, underwent evaluation and was found to have Lp(a)∼1.8x ULN, a normal lipid profile, and unremarkable coronary computed tomography angiogram (CTA).

Results

Case Presentation 2/2: All three underwent Allelica Inc. PRS, revealing 99th percentile, 91st percentile, and 64th percentile respective CAD risk. All three family members continue to be treated with pharmacotherapy and are doing well.

Conclusions

In this case, no monogenic variant was identified to explain AA's hyperlipidemia. PRS strongly correlated with the clinical phenotypes of the family members, helping to potentially explain the differential atherosclerotic burden between the two sisters. In this context, there is no urgency for intensive pharmacotherapy for the unaffected sister. PRS is a growing part of CV risk stratification, providing valuable insight in families with a substantial premature CAD burden. It represents an important complementary tool in risk stratification and can be used in conjunction with genetic testing for monogenic lipid disorders.