Genetic, sociodemographic, lifestyle, and clinical risk factors of recurrent coronary artery disease events: a population-based cohort study

Abstract

Aims: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence.

Methods and results: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD (0.74, 0.67-0.82). Additionally, age at enrolment, CAD PRS, C-reactive protein, lipoprotein(a), glucose, low-density lipoprotein cholesterol, deprivation, sleep quality, eGFR, and high-density lipoprotein (HDL) cholesterol also significantly associated with recurrence risk. Based on C indices (95% CI), the strongest predictors were CAD PRS (0.58, 0.57-0.59), HDL cholesterol (0.57, 0.57-0.58), and age at initial CAD event (0.57, 0.56-0.57). In addition to traditional risk factors, a comprehensive model improved the C index from 0.644 (0.632-0.654) to 0.676 (0.667-0.686).

Conclusion: Sociodemographic, clinical, and laboratory factors are each associated with CAD recurrence with genetic risk, age at first CAD event, and HDL cholesterol concentration explaining the most.

Keywords: Coronary artery disease; Epidemiology; Preventive cardiology; Risk prediction; Secondary prevention.

Structured Graphical Abstract

BMI body mass index; CAD coronary artery disease; eGFR estimated glomerular filtration rate; HDLc high-density lipoprotein cholesterol; hsCRP high-sensitivity C-reactive protein; LDLc low-density lipoprotein cholesterol; Lp(a) lipoprotein(a); PRS polygenic risk score; SBP systolic blood pressure

Figure 1

Possible timeline of recurrent CAD events included in the analysis. Scenario A describes participants with single CAD event prior to UK Biobank enrolment and first and only recurrence (denoted with red *) after enrolment. Scenario B describes participants with multiple CAD events prior to enrolment and one recurrence (red *) after enrolment. Scenarios A and B are considered recurrent CAD cases. However, scenario C describes participants with first and only CAD event prior to enrolment and without recurrence thereafter. Recurrence criteria within 28 days of the most recent event prior to enrolment is considered a bundled event from the same episode, thereby disregarded. Abbreviation: CAD, coronary artery disease.

Figure 2

Predicted effect of individual risk factor on CAD recurrence risk. Categorical predictors are computed as binary variable. All models are based on Cox proportional hazards model adjusting for age at UK Biobank enrolment, age at first CAD event, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, systolic blood pressure, LDL and HDL cholesterols, triglycerides, glucose, lipoprotein(a), hsCRP, eGFR, statin prescription, the first 10 principal components, genotyping array, and CAD PRS. Abbreviations: CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; PRS, polygenic risk score; TDI, Townsend Deprivation Index.

Figure 3

Association of sociodemographic, lifestyle, clinical, and genetic risk factors with risk of recurrent CAD events. Categorical predictors are computed as binary variable. HRs are adjusted for age at enrolment, age at first CAD event, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, glucose, lipoprotein(a), hsCRP, eGFR, statin prescription, the first 10 principal components, genotyping array, and CAD PRS. The colour gradient represents the magnitude of effect estimates. Abbreviations: CAD, coronary artery disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; HR, hazard ratio; hsCRP, high sensitivity C-reactive protein; LDL, low-density lipoprotein; PRS, polygenic risk score.

Figure 4

(A) Discrimination ability and (B) relative importance of individual genetic, sociodemographic, lifestyle, and clinical risk factors for predicting recurrent CAD events. The discrimination C index estimates the probability of a model assigning a higher risk to participants who undergoes CAD recurrence compared to those without recurrence. The estimated explained relative risk (R²) reflects the strength of the association for risk factors for predicting CAD recurrence. R² was calculated based on the entropy loss function and the Kullback–Leibler information gain. All indexes are based on Cox proportional hazards model adjusting for age at UK Biobank enrolment, age at first CAD event, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, systolic blood pressure, LDL and HDL cholesterols, triglycerides, glucose, lipoprotein(a), hsCRP, eGFR, statin prescription, the first 10 principal components, genotyping array, and CAD PRS. Abbreviations: CAD, coronary artery disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; hsCRP, high sensitivity C-reactive protein; LDL, low-density lipoprotein; PRS, polygenic risk score.