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. 2023 Oct 26;30(15):1571-1579.
doi: 10.1093/eurjpc/zwad096.

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

Amanda R Jowell  1 , Romit Bhattacharya  1   2   3 , Christopher Marnell  4   5 , Megan Wong  2   3 , Sara Haidermota  2   3 , Mark Trinder  2   3   6 , Akl C Fahed  1   2   3 , Gina M Peloso  7 , Michael C Honigberg  1   2   3 , Pradeep Natarajan  1   2   3
Affiliations

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

Amanda R Jowell et al. Eur J Prev Cardiol. .

Abstract

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

Methods and results: 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 [PRSCAD], 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 PRSCAD (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.

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

Keywords: Cardiovascular disease; Family history of heart disease; Genetics; Polygenic risk score; Prevention; Risk factor; UK Biobank.

Plain language summary

With advances in genetics, it is tempting to assume that the ‘family history’ of a patient is an imperfect proxy for information we can already glean from genetics and laboratory tests. However, this study shows that much of the information contained in the self-reported family history of heart disease is not captured by currently available genetic and clinical biomarkers and highlights an important knowledge gap. Clinically used biomarkers explained only 21.9% of the likelihood of a patient reporting a family history of heart disease, while genetics explained 22.2%, and a combined model explained 36% of this likelihoodThe majority of the risk of reporting a family history went unexplained, implying that family history still has major relevance in clinical practice.

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Conflict of interest statement

Conflict of interest: R.B. is a medical advisor to Casana Care Inc, unrelated to present work. A.C.F. holds equity and receives consulting fees from Goodpath, and receives research funding from Abbott Inc., both unrelated to this study. M.C.H. reports consulting fees from CRISPR Therapeutics and serves on the advisory board for Miga Health, both unrelated to this work. P.N. reports investigator-initiated grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis. personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Novartis, Roche/Genentech, is a co-founder of TenSixteen Bio, is a scientific advisory board member of Esperion Therapeutics, geneXwell, and TenSixteen Bio, and spousal employment at Vertex, all unrelated to this work.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Population attributable risk percent for family history of heart disease by individual risk factors. Here, we present the population attributable risk for each risk factor, individually modeled for reported family history of heart disease, controlling for age and sex. For all continuous variables, the top four quintiles were compared to the bottom quintile, as indicated by [2nd–5th quintiles vs. 1st quintile (reference)]. A lower bound of 0 was created for PAR.
Figure 1
Figure 1
Study population. The UK Biobank is a population-based cohort of adults who follow prospectively, with ages ranging between 40 and 70 years. Abbreviations: CAD, coronary artery disease; FHHD, family history of heart disease; WES, whole exome sequencing; PAR, population attributable risk; PRSCAD, polygenic risk score for coronary artery disease; Lp(a), Lipoprotein(a) nmol/L.
Figure 2
Figure 2
Graded relationship between the number of family members with (A) incident CAD and (B) polygenic risk score for CAD. χ2-test for trend was significant to P < 0.001 for both (A) and (B). Average follow-up time 10.7 years. Abbreviations: CAD, coronary artery disease; PRSCAD, polygenic risk score of coronary artery disease.
Figure 3
Figure 3
(A) Distribution of PRSCAD scores, and (B) odds of family history of HD being present after adjustment for age, sex, cholesterol medication use, ever-smoking, hypertension, diabetes, waist-to-hip ratio, triglycerides, and heterozygous familial HeFH, ApoB:ApoA1 ratio, lp(a), and hsCRP level. ApoB:ApoA1, apolipoprotein B-to-apolipoprotein AI ratio; Lp(a), lipoprotein(a): hsCRP, high sensitivity C-reactive protein, PAR, population attributable risk.
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Comment in

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