A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction

作者：Coassin Stefan; Erhart Gertraud; Weissensteiner Hansi; de Araujo Mariana Eca Guimaraes; Lamina Claudia; Schoenherr Sebastian; Forer Lukas; Haun Margot; Losso Jamie Lee; Koettgen Anna; Schmidt Konrad; Utermann Gerd; Peters Annette; Gieger Christian; Strauch Konstantin; Finkenstedt Armin; Bale Reto; Zoller Heinz; Paulweber Bernhard; Eckardt Kai Uwe; Huettenhofer Alexander; Huber Lukas A; Kronenberg Florian^*

来源：European Heart Journal, 2017, 38(23): 1823-+.

DOI：10.1093/eurheartj/ehx174

• Lipoprotein(a)
• LPA
• CVD risk
• Kringle IV-type 2
• Copy number variation

Aims Lp(a) concentrations represent a major cardiovascular risk factor and are almost entirely controlled by one single locus (LPA). However, many genetic factors in LPA governing the enormous variance of Lp(a) levels are still unknown. Since up to 70% of the LPA coding sequence are located in a difficult to access hypervariable copy number variation named KIV-2, we hypothesized that it may contain novel functional variants with pronounced effects on Lp(a) concentrations. We performed a large scale mutation analysis in the KIV-2 using an extreme phenotype approach
Methods and results We compiled an discovery set of 123 samples showing discordance between LPA isoform phenotype and Lp(a) concentrations and controls. Using ultra-deep sequencing, we identified a splice site variant (G4925A) in preferential association with the smaller LPA isoforms. Follow-up in a European general population (n = 2892) revealed an exceptionally high carrier frequency of 22.1% in the general population. The variant explains 20.6% of the Lp(a) variance in carriers of low molecular weight (LMW) apo(a) isoforms (P = 5.75e-38) and reduces Lp(a) concentrations by 31.3 mg/dL. Accordingly the odds ratio for cardiovascular disease was reduced from 1.39 [95% confidence interval (CI): 1.17-1.66, P = 1.89e-04] for wildtype LMW individuals to 1.19 [95% CI: 0.92; 1.56, P = 0.19] in LMW individuals who were additionally positive for G4925A. Functional studies point towards a reduction of splicing efficiency by this novel variant.
Conclusion A highly frequent but until now undetected variant in the LPA KIV-2 region is strongly associated with reduced Lp(a) concentrations and reduced cardiovascular risk in LMW individuals.

• 出版日期2017-6-14
• 单位河北医科大学