Pia R Kamstrup1, Anne Tybjærg-Hansen2, Børge G Nordestgaard3. 1. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark. 2. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: Boerge.Nordestgaard@regionh.dk.
Abstract
OBJECTIVES: The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS). BACKGROUND: The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS. METHODS: We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design. RESULTS:Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels. CONCLUSIONS:Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk.
RCT Entities:
OBJECTIVES: The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS). BACKGROUND: The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS. METHODS: We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design. RESULTS: Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels. CONCLUSIONS: Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk.
Keywords:
AVS; CI; ICD; International Classification of Diseases; KIV-2; Lp(a); SNP; aortic valve stenosis; confidence interval; genes; kringle IV type 2; single nucleotide polymorphism
Authors: Teresa Trenkwalder; Christopher P Nelson; Muntaser D Musameh; Ify R Mordi; Thorsten Kessler; Costanza Pellegrini; Radoslaw Debiec; Tobias Rheude; Viktor Lazovic; Lingyao Zeng; Andreas Martinsson; J Gustav Smith; Jesper R Gådin; Anders Franco-Cereceda; Per Eriksson; Jonas B Nielsen; Sarah E Graham; Cristen J Willer; Kristian Hveem; Adnan Kastrati; Peter S Braund; Colin N A Palmer; Amparo Aracil; Oliver Husser; Wolfgang Koenig; Heribert Schunkert; Chim C Lang; Christian Hengstenberg; Nilesh J Samani Journal: Int J Cardiol Date: 2018-11-17 Impact factor: 4.164