Integrating Indices of Genetic Risk for Cardiovascular Disease

Corresponding Author

Indeed, as our understanding of ASCVD riskenhancing factors has expanded, it has become clear that conventional risk estimation fails to capture certain key predictors of atherosclerosis, including much of the contribution of genetics to heart disease.
In contemporary practice, querying family history of heart disease, especially when premature, represents a commonly used screen for heritable risk, although recent data suggest that the majority of family history of coronary heart disease (CHD) may in fact represent shared nongenetic risk factors, such as environment and group behaviors. 5Rare pathogenic variants in key genes involved in cholesterol metabolism, chiefly LDLR, APOB, and PCSK9, underlie classical "monogenic" familial hypercholesterolemia (FH), whereby single gene mutations confer large effects on circulating atherogenic lipoproteins and associated risk of premature ASCVD events.Whether driven by monogenic FH or otherwise, a low-density lipoprotein cholesterol (LDL-C) $190 mg/dL represents a Class I guideline indication for statin therapy to reduce lifetime ASCVD risk. 2 More recently, large genotyped data sets have enabled genome-wide association studies (GWAS) of CHD, implicating biologic pathways that operate independent of conventional ASCVD risk factors.In turn, GWAS have enabled derivation of polygenic risk scores (PRS), which are continuous, normally distributed measures of aggregate genetic risk for disease conferred by variation across the genome (Figure 1).PRS independently predict risk for an array of cardiometabolic diseases, 6 with the top w5% of CHD PRS representing similar risk for CHD as monogenic FH. 7 Although germline genetic risk is non-modifiable, evidence consistently suggests that addressing other modifiable risk factors is effective at offsetting heightened genetic risk.As elevated PRS is substantially more common than FH, incorporating this genetic information may augment the predictive utility of conventional ASCVD scores.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate.For more information, visit the Author Center.
In this issue of JACC: Advances, Saadatagah et al8 analyze the utility of CHD PRS in predicting incident CHD, and whether the risks conferred by monogenic FH and history of CHD in a first-degree relative were independent of, and additive to, CHD PRS.In line with current state-of-the-art approaches, the authors used a previously published genome-wide CHD PRS incorporating 1.7 million variants.Among 323,373 primary prevention genotyped individuals in the UK Biobank (UKB), addition of PRS to the PCE improved the C-statistic for CHD from 0.759 to 0.773 (P < 0.001), up-classified 5.4% of individuals above the 7.5% threshold of 10-year ASCVD risk, and down-classified ISSN 2772-963X https://doi.org/10.1016/j.jacadv.2023.100568*Editorials published in JACC: Advances reflect the views of the authors and do not necessarily represent the views of JACC: Advances or the American College of Cardiology.From the a Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; b Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; and the c Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

FIGURE 1 3 Integrating
FIGURE 1 Polygenic Risk, Monogenic Risk Variants, and Family History Confer Independent Risk for Coronary Heart Disease in the Primary Cardiovascular Prevention Population E ( h t t p : / / c r e a t i v e c o m m o n s .o r g / l i c e n s e s / b y / 4 .0 / ) .
11rated as a risk-enhancing factor and CHD PRS may represent an additional risk-enhancing factor to upclassify risk and guide statin prescribing.10Furthermore,amongthosewith established ASCVD (ie, the secondary prevention population), recent data indicate that high PRS may predict residual risk for recurrent ASCVD events,11implying that PRS may