Abstract 10667: Mendelian Randomization of Lp(a) Levels and Coronary Disease Risk
Background: Genetic studies have identified single nucleotide polymorphisms (SNPs) at the LPA locus related to lipoprotein(a) [Lp(a)] levels and coronary artery disease (CAD) risk. We performed a Mendelian randomization analysis to explore the shape, strength and causal relationship of SNPs at the LPA locus and Lp(a) levels with CAD risk in 6342 individuals from the PROCARDIS study.
Methods and results: We examined the effects of 7 SNPs at the LPA locus previously shown to be strongly and independently related to Lp(a) levels (and account for 40% of the variance) with additional unpublished data on Lp(a) levels in 3051 CAD cases and 3291 controls. We constructed a weighted genotype score involving the 7 SNPs and classified individuals into 3 groups corresponding to the observed tri-modal distribution of the LPA score. Individuals were also classified by categories of observed plasma levels of Lp(a) (<10mg/dL, 10-30mg/dL, 30-50mg/dL, 50-70mg/dL and >70mg/dL). Figure 1 shows an approximately log-linear relationship of CAD risk with Lp(a) levels across the LPA score groups, consistent with a 15% lower CAD risk per 10mg/dL lower Lp(a) level. The shape and strength of the association of CAD risk with Lp(a) levels across the Lp(a) categories was concordant with that estimated using the LPA score groups. Furthermore, after adjustment for Lp(a) levels, the association of the LPA score with CAD risk was completely attenuated (Chi-squared:79.4 vs 3.26).
Conclusions: More than one in five persons carry LPA variants that confer about a two-fold or higher risk of CAD, and this excess risk can be explained by Lp(a) levels. Agents such as niacin and CETP inhibitors lower Lp(a) by 30-40% and therefore have the potential to reduce CAD risk considerably, particularly for those with higher Lp(a) levels. Figure 1: Association of CAD risk with Lp(a) levels across (i) LPA score groups [black boxes] and (ii) categories of observed Lp(a) level [white boxes].
- © 2011 by American Heart Association, Inc.