Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification

Abstract

Importance: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown.

Objective: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification.

Design, setting, and participants: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018.

Exposures: Case-control studies.

Main outcomes and measures: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography.

Results: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006).

Conclusions and relevance: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.

Trial registration: ClinicalTrials.gov NCT00338676 NCT00647088.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Arsenault holds a junior scholar award from the Fonds de Recherche du Québec: Santé and has received research funding from the Canadian Institutes of Health Research, Pfizer, Merck, and Ionis Pharmaceuticals. Dr Thériault holds a junior scholar award from the Fonds de Recherche du Québec: Santé. Dr Clavel holds a junior scholar award from the Fonds de Recherche du Québec: Santé. Ms Després is supported by a master’s training award from the Fonds de Recherche du Québec: Santé. Dr Mathieu holds a Fonds de Recherche du Québec: Santé Research Chair on the Pathobiology of Calcific Aortic Valve Disease. Dr Pibarot holds the Canada Research Chair in Valvular Heart Disease, and his research program is supported by a Foundation Scheme Grant from the Canadian Institutes of Health Research. Dr Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases. Dr Capoulade is supported by a Connect Talent research chair from Région Pays de la Loire and Nantes Métropole. Dr Thanassoulis is supported by grant R01 HL128550 from the National Heart, Blood, and Lung Institute and reports receiving grants from Ionis during the conduct of the study, as well as personal fees from Amgen and Sanofi and grants from Servier, outside the submitted work. Dr Chen reported receiving studentships from the McGill University Health Centre Research Institute, McGill University Health Centre Foundation, and McGill University Faculty of Medicine during the conduct of the study. Dr Le Tourneau reported personal fees from Bayer and Pfizer and grants from Abbott–St Jude outside the submitted work. Dr Messika-Zeitoun reported grants from Programme Hospitalier de Recherche Clinique from Assistance Publique–Hôpitaux de Paris during the conduct of the study and grants and personal fees from Edwards outside the submitted work. Dr Khaw reported grants from Medical Research Council UK during the conduct of the study. Dr Wareham reported grants from Medical Research Council during the conduct of the study. Dr Pibarot reported grants from Edwards Life Sciences outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Association of Genetically Elevated Lipoprotein(a) Levels With Calcific Aortic Valve Stenosis in Individuals With Coronary Artery Disease and Those Without Coronary Artery Disease

CAVS indicates calcific aortic valve stenosis; EPIC-Norfolk, European Prospective Investigation of Cancer–Norfolk; GERA, Genetic Epidemiology Research on Aging; QUEBEC-CAVS, the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec; UK, United Kingdom.

Figure 2.. Association of Genetically Elevated Lipoprotein(a) Levels With Calcific Aortic Valve Stenosis in Study Subgroups

Patients with coronary artery disease and without coronary artery disease in the French cohorts, compared with control participants. CAVS indicates calcific aortic valve stenosis.

Figure 3.. Distribution of Participant and Comparison Groups

A, Distribution of patients with calcific aortic valve stenosis (CAVS) or a tissue to background (TBR) ratio of 1.25 or greater in the family study. B, Mean aortic valve TBR ratio in first-degree relatives without CAVS and control participants with low lipoprotein(a) (Lp[a]) levels.

Figure 4.. Study Schematic

Results of this study that included cohorts from 4 countries suggest that the association between genetically elevated lipoprotein(a) (Lp[a]) levels and calcific aortic valve stenosis (CAVS) is comparable in patients with coronary artery disease (CAD) vs those without and that first-degree relatives of patients with high Lp(a) levels and CAVS may have higher aortic valve calcification and could be at higher future risk of aortic valve calcification or CAVS.