TY - JOUR
T1 - Common gene variants in ASGR1 gene locus associate with reduced cardiovascular risk in absence of pleiotropic effects
AU - Ali, Lubna
AU - Cupido, Arjen J.
AU - Rijkers, Maaike
AU - Hovingh, G. Kees
AU - Holleboom, Adriaan G.
AU - Dallinga-Thie, Geesje M.
AU - Stroes, Erik S. G.
AU - van den Boogert, Marjolein A. W.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Background and aims: The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization. Methods: Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores. Results: Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62–0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR. Conclusions: Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels.
AB - Background and aims: The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization. Methods: Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores. Results: Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62–0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR. Conclusions: Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels.
KW - ASGR1
KW - Cardiovascular disease
KW - LDL cholesterol
KW - Mendelian randomization
KW - Platelets
UR - http://www.scopus.com/inward/record.url?scp=85087743895&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.atherosclerosis.2020.07.001
DO - https://doi.org/10.1016/j.atherosclerosis.2020.07.001
M3 - Article
C2 - 32679274
SN - 0021-9150
VL - 306
SP - 15
EP - 21
JO - Atherosclerosis
JF - Atherosclerosis
ER -