High Lp(a) confers greater risk for early ACS when LDL-C is elevated
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
BackgroundIncreased 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) . There is limited evidence that supports the recommended control of other risk factors, like LDL-C, in case of elevated Lp(a) .
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].
- 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)
ConclusionIn 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.
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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;31:2844–2853
2. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009;301:2331–2339
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;368:503–512
4. Brown WV, Ballantyne CM, Jones PH, et al. Management of Lp(a). J Clin Lipidol. 2010;4:240–247
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;5:338–367
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;144:207–213
7. Yang Q, Khoury MJ, Flanders WD. Sample size requirements in case-only designs to detect gene-environment interaction. Am J Epidemiol. 1997;146:713–720
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;90:52–60
9. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: metaanalysis of prospective studies. Circulation. 2000;102:1082–1085
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;40:571–573
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;47:1098–1099