The interactions of Lipoprotein(a) with common cardiovascular risk factors in cardiovascular disease risk: evidence based on the UK Biobank

Abstract

Background: : Although Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease, it is unclear whether the associated risk is similar in the presence of other concomitant risk factors. Here, we aimed to investigate the interactions between Lp(a) and common cardiovascular risk factors on coronary artery disease (CAD), calcific aortic valve stenosis (CAVS) and ischemic stroke (IS).

Methods: : We included 127,958 unrelated European-ancestry participants from UK Biobank (54.7 % women) with data available on Lp(a) and without a baseline history of CAD, CAVS and IS. Multivariable-adjusted Cox proportional hazards interaction models were used to study whether the associations of Lp(a) with outcomes varied based on the level of total cholesterol (Total-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG) and other cardiovascular risk factors.

Results: : Higher Lp(a) levels were associated with higher risks of CAD, CAVS and IS. Per 10 mg/dL increase in Lp(a), hazard ratios [95 % confidence interval] were 1.05 [1.04, 1.06], 1.06 [1.04, 1.09], and 1.01 [0.99, 1.03] for CAD, CAVS and IS, respectively. For CAD, interactions were observed between Lp(a) and Total-C (P_interaction =0.001), LDL-C (P_interaction =4e-4) and TG (P_interaction =0.026). In more detail, participants with Lp(a) ≥ 50 mg/dL in the highest quartile of Total-C, LDL-C and TG showed evidence of additive interaction in CAD, with relative excess risk due to interaction (RERI) of 0.42 (0.17, 0.67), 0.44 (0.18, 0.71), and 0.39 (0.12, 0.67), respectively. No such interactions were observed in CAVS and IS.

Conclusions: Lp(a)-associated CAD risk seems to particularly affect those having levels of Total-C, LDL-C and TG above the thresholds from clinical guidelines.

Keywords: Calcific aortic valve stenosis; Common cardiovascular risk factors; Coronary artery disease; Interaction effects; Lipoprotein(a) risk.

Graphical abstract

Fig. 1

The interactions between Lp(a) and the common cardiovascular risk factors, and the risk of developing coronary artery disease for per 10 mg/dL increase of Lp(a) in subgroups. Abbreviations: BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HbA1c: glycated haemoglobin; HD: heart disease; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SBP: systolic blood pressure; Total-C, total cholesterol; TG, triglycerides. LDL-C_cor and Total-C_cor represent the corrected LDL-C and Total-C. The ‘IncidenceRate’ shows the incidence rate of developing CAD per 100,000 person-years in different subgroups. The ‘Heterogeneity’ shows the P-values of χ² tests for HRs among subgroups. The ‘InteractionTerm’ shows the P-values of tests for the interaction terms between Lp(a) and the original risk factors.

Fig. 2

The joint effects between Lp(a) and (A) Total-C, (B) LDL-C, and (C) TG on coronary artery disease. LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); Total-C, total cholesterol; TG, triglycerides. Hazard ratios were calculated using Cox proportional hazards regression analysis after adjusting for age, sex, Townsend index, smoking status, alcohol consumption frequency, and physical activity. Individuals with Lp(a) < 30 mg/dL and lowest levels of (A) Total-C, (B) LDL-C and (C) TG are the reference group. * indicated P < 0.05, ** indicated P < 0.01, *** indicated P < 0.001, **** indicated P < 0.0001.

Fig. 3

The interactions between LPA GRS and the common cardiovascular risk factors, and the risk of developing coronary artery disease for per one-SD increase of LPA GRS in subgroups. Abbreviations: BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; HbA1c: glycated haemoglobin; HD: heart disease; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SBP: systolic blood pressure; Total-C, total cholesterol; TG, triglycerides. LDL-C_cor and Total-C_cor represent the corrected LDL-C and Total-C. The ‘IncidenceRate’ shows the incidence rate of developing CAD per 100,000 person-years in different subgroups. The ‘Heterogeneity’ shows the P-values of χ² tests for HRs among subgroups. The ‘InteractionTerm’ shows the P-values of tests for the interaction terms between LPA GRS and the original risk factors.