Inflammatory IL-1 genotype doubles the cardiovascular risk from high Lp(a), the Ioannina Study of 603 patients (J Clin Lipidol 2018)

Original title: Interleukin-1 genotypes modulate the long-term effect of lipoprotein(a) on cardiovascular events: The Ioannina Study

J Clin Lipidol · 19 December 2017 · 7

Naka KK, Bechlioullis A, Marini A, Sionis D, Vakalis K, Triantis G, Wilkins L, Rogus J, Kornman KS, Witztum JL, Doucette-Stamm L, Michalis LK et al.

The Ioannina Study measured interleukin-1 (IL-1) genotypes and Lp(a) in 603 patients without diabetes undergoing coronary angiography, followed for a median 45 months, to test whether proinflammatory IL-1 genotypes modulate Lp(a)-mediated cardiovascular risk. Overall, higher Lp(a) (top versus bottom quartile) was associated with major adverse cardiovascular events (hazard ratio 2.95, 95% CI 1.16-7.54, P=.023) and coronary artery disease (odds ratio 1.84, 95% CI 1.12-3.03, P=.016). Patients with the proinflammatory IL-1(+) genotype and Lp(a) above the median (9.2 mg/dL) had markedly worse event-free survival than IL-1(-) patients with low Lp(a) (hazard ratio 3.59, 95% CI 1.07-12.03, P=.039), and in IL-1(+) patients aged 60 or younger, higher Lp(a) was also associated with coronary disease (odds ratio 2.90, 95% CI 1.07-7.86, P=.036), an association absent in IL-1(-) patients. The findings show proinflammatory IL-1(+) genotypes amplify Lp(a)-related cardiovascular risk, identifying younger patients with both elevated Lp(a) and this genotype as a particularly high-risk group.

Original abstract

Background: Lipoprotein(a) [Lp(a)] is a genetic risk factor for cardiovascular disease (CVD), and proinflammatory interleukin-1 (IL-1) genotypes may influence Lp(a)-mediated CVD events. The genotype IL-1(+) is associated with higher rates of inflammation than IL-1(-) genotype. Targeting IL-1β was recently shown to decrease CVD events independent of low-density lipoprotein-cholesterol levels.

Objective: The objective of the study is to assess the modulatory effect of IL-1 genotypes on risk mediated by Lp(a) METHODS: We assessed whether IL-1 genotypes modulate the effect of Lp(a) on major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke/transient ischemic attack) and angiographically determined coronary artery disease (CAD). IL-1 genotypes and Lp(a) were measured in 603 patients without diabetes mellitus undergoing angiography. Major adverse cardiovascular events and CAD were assessed over a median of 45 months.

Results: In multivariable-adjusted analysis, Lp(a) was associated with major adverse cardiovascular events (hazard ratio [HR] [95% confidence interval {CI}]: 2.95 [1.16-7.54], P = .023) and CAD (odds ratio [OR] [95% CI]: 1.84 [1.12-3.03], P = .016) comparing quartile 4 vs quartile 1. In Cox regression analysis, IL-1(+) patients with Lp(a) above the median (>9.2 mg/dL) had a worse event-free cumulative survival (HR [95% CI]: 3.59 [1.07-12.03], P = .039) compared to IL-1(-) patients with Lp(a) below the median. In IL-1(+) patients aged ≤60 years, Lp(a) was also associated with angiographically determined CAD (OR [95% CI]: 2.90 [1.07-7.86], P = .036) comparing quartile 4 vs quartile 1 but not IL-1(-) patients.

Conclusion: Proinflammatory IL-1(+) genotypes modulate the risk of Lp(a) long-term CVD events and CAD. These data suggest that the dual genetic contributions of elevated Lp(a) levels and IL-1(+) genotypes may identify younger subjects at particularly high risk for CVD events.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.