Genetic and clinical factors underlying a self-reported family history of heart disease

To estimate how much information conveyed by self-reported family history of heart disease (FHHD) is already explained by clinical and genetic risk factors.

Cross-sectional analysis of UK Biobank participants without pre-existing coronary artery disease using a multivariable model with self-reported FHHD as the outcome. Clinical (diabetes, hypertension, smoking, apolipoprotein B-to-apolipoprotein AI ratio, waist-to-hip ratio, high sensitivity C-reactive protein, lipoprotein(a), triglycerides) and genetic risk factors (polygenic risk score for coronary artery disease [PRS_CAD], heterozygous familial hypercholesterolemia [HeFH]) were exposures. Models were adjusted for age, sex, and cholesterol-lowering medication use. Multiple logistic regression models were fitted to associate FHHD with risk factors, with continuous variables treated as quintiles. Population attributable risks (PAR) were subsequently calculated from the resultant odds ratios. Among 166 714 individuals, 72 052 (43.2%) participants reported an FHHD. In a multivariable model, genetic risk factors PRS_CAD (OR 1.30, CI 1.27–1.33) and HeFH (OR 1.31, 1.11–1.54) were most strongly associated with FHHD. Clinical risk factors followed: hypertension (OR 1.18, CI 1.15–1.21), lipoprotein(a) (OR 1.17, CI 1.14–1.20), apolipoprotein B-to-apolipoprotein AI ratio (OR 1.13, 95% CI 1.10–1.16), and triglycerides (OR 1.07, CI 1.04–1.10). For the PAR analyses: 21.9% (CI 18.19–25.63) of the risk of reporting an FHHD is attributed to clinical factors, 22.2% (CI% 20.44–23.88) is attributed to genetic factors, and 36.0% (CI 33.31–38.68) is attributed to genetic and clinical factors combined.

A combined model of clinical and genetic risk factors explains only 36% of the likelihood of FHHD, implying additional value in the family history.