Lipoprotein(a) Levels, Genotype and Incident Aortic Valve Stenosis: A Prospective Mendelian Randomization Study and Replication in a Case-Control Cohort
Background—Although a previous study has suggested that a genetic variant in the LPA region was associated with the presence of AVS, no prospective study has suggested a role for Lp(a) levels in the pathophysiology of AVS. Our objective was to determine whether lipoprotein (a) [Lp(a)] levels and a common genetic variant that is strongly associated with Lp(a) levels are associated with an increased risk of developing aortic valve stenosis (AVS).
Methods and Results—Serum Lp(a) levels were measured in 17,553 participants of the EPIC-Norfolk study. Among these study participants, 118 developed AVS during a mean follow-up of 11.7 years. The rs10455872 genetic variant in LPA was genotyped in 14,735 study participants who simultaneously had Lp(a) levels measurements and in a replication study of 379 patients with echocardiography-confirmed AVS and 404 controls. In EPIC-Norfolk, compared to participants in the bottom Lp(a) tertile, those in the top Lp(a) tertile had a higher risk of AVS; hazard ratio (HR) 1.57 [95% CI, 1.02-2.42] after adjusting for age, sex and smoking. Compared to rs10455872 AA homozygotes, carriers of one or two G alleles were at increased risk of AVS; HR=1.78 [1.11-2.87] and HR=4.83 [1.77-13.20], respectively. In the replication study, the genetic variant rs10455872 also showed a positive association with AVS (odds ratio=1.57 [1.10-2.26]).
Conclusions—Patients with high Lp(a) levels are at increased risk for AVS. The rs10455872 variant which is associated with higher Lp(a) levels is also associated with increased risk of AVS, suggesting that this association may be causal.
- Received October 24, 2013.
- Revision received January 8, 2014.
- Accepted March 18, 2014.