Physicians' Academy for Cardiovascular Education

High Lp(a) confers greater risk for early ACS when LDL-C is elevated

Afshar M et al., J Am Heart Assoc. 2016

Lipoprotein(a) Interactions With Low-Density Lipoprotein Cholesterol and Other Cardiovascular Risk Factors in Premature Acute Coronary Syndrome (ACS)

Afshar M, Pilote L, Dufresne L, et al.
J Am Heart Assoc. 2016; published online ahead of print


Increased Lp(a) is a common genetic dyslipidemia that has been associated with CVD risk [1-3], however there are finite therapeutic options for the management of elevated Lp(a) [4]. There is limited evidence that supports the recommended control of other risk factors, like LDL-C, in case of elevated Lp(a) [5].
It is hypothesised that the identification of interactions between Lp(a) and other CV risk factors could identify individuals at increased risk for Lp(a)-mediated disease, and help develop strategies to attenuate the risk conferred by high Lp(a) levels. .
In this case-only design study, it was evaluated whether high Lp(a) interacts with LDL-C levels and other ACS risk factors in 939 participants of the GENESIS-PRAXY (GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond-Premature Acute Coronary Syndrome) study. A case-only design study can identify interactions between genes and the environment, when genetic and environmental exposure are not associated in the general population [6,7]. Lp(a) is under strong genetic regulation and was not influenced by most CV risk factors, including LDL-c in the general population [8-11].

Main results

  • There was a higher prevalence of elevated Lp(a) levels (>50 mg/dL; 80th percentile) in GENESIS-PRAXY participants compared with the general population (31% versus 20%; P<0.001)
  • Lp(a) was strongly associated with LDL-C (adjusted β: 0.17; P<0.001)
  • In logistic regression analysis, individuals with high Lp(a) >50 mg/dL were more likely to have LDL-C >2.5 mmol/L, indicating a synergistic interaction: unadjusted OR: 1.53; 95% CI: 1.11–2.11; P=0.009, adjusted OR: 1.51; 95% CI: 1.08–2.09; P=0.015
  • In sensitivity analyses, the interaction with high Lp(a) was stronger at increasing LDL-C levels. The adjusted odds ratio increased: from 1.51 (95% CI: 1.08–2.09; P=0.015) at LDL-C >2.5 mmol/L to 2.72 (95% CI: 1.67–4.42; P<0.001) at LDL-C >4.5 mmol/L
  • The interaction with high Lp(a) became attenuated at LDL-C ≤3.5 mmol/L in a polytomous logistic model. As compared to LDL-C <2.5 mmol/L, adjusted Lp(a) interaction odds ratios across LDL-C groups were for LDL-C 2.5-3.5 mmol/L: 1.16 (95%CI: 0.80–1.68; P=0.447), for LDL-C 3.5-4.5 mmol/L: 1.66 (95%CI: 1.11–2.51; P=0.015) and for LDL-C >4.5 mmol/L: 3.31 (95% CI: 1.93–5.67; P<0.001).
  • Other risk factors were not associated with high Lp(a)


In young ACS patients, high Lp(a) is more prevalent than in the general population and is strongly associated with high LDL-C. These findings suggest that Lp(a) confers a greater risk for ACS when LDL-C is elevated. LDL-C lowering therapy in individuals with high Lp(a) and LDL-C >3.5 mmol/L may yield meaningful reductions of premature CV risk.
Find this article online at JAHA


1. Nordestgaard BG, Chapman MJ, Ray K, Boren J, et al. European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:28442853
2. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:23312339
3. Thanassoulis G, Campbell CY, Owens DS, et al. CHARGE Extracoronary Calcium Working Group.
Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503512
4. Brown WV, Ballantyne CM, Jones PH, et al. Management of Lp(a). J Clin Lipidol. 2010;4:240247
5. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338367
6. Khoury MJ, Flanders WD. Non-traditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls. Am J Epidemiol. 1996;144:207213
7. Yang Q, Khoury MJ, Flanders WD. Sample size requirements in case-only designs to detect gene-environment interaction. Am J Epidemiol. 1997;146:713720
8. Boerwinkle E, Leffert CC, Lin J, et al. Apolipoprotein (a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1992;90:5260
9. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: metaanalysis of prospective studies. Circulation. 2000;102:10821085
10. Li KM, Wilcken DEL, Dudman NPB. Effect of serum lipoprotein(a) on estimation of low-density lipoprotein cholesterol by the Friedewald formula. Clin Chem.1994;40:571573
11. Saeedi R, Li M, Allard M, Frohlich J. Marked effects of extreme levels of lipoprotein(a) on estimation of low-density lipoprotein cholesterol. Clin Biochem. 2014;47:10981099