TY - JOUR
T1 - Variants in the
GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.
AU - Rimbert, Antoine
AU - Yeung, Ming W
AU - Dalila, Nawar
AU - Thio, Chris H L
AU - Yu, Haojie
AU - Loaiza, Natalia
AU - Oldoni, Federico
AU - van der Graaf, Adriaan
AU - Wang, Siqi
AU - Said, M Abdullah
AU - Blauw, Lisanne L
AU - Girardeau, Aurore
AU - Bray, Lise
AU - Caillaud, Amandine
AU - Bloks, Vincent W
AU - Marrec, Marie
AU - Moulin, Philippe
AU - Rensen, Patrick C N
AU - van de Sluis, Bart
AU - Snieder, Harold
AU - Di Filippo, Mathilde
AU - van der Harst, Pim
AU - Tybjaerg-Hansen, Anne
AU - Zimmerman, Philip
AU - Cariou, Bertrand
AU - Kuivenhoven, Jan Albert
N1 - Funding Information:
This work was supported by grants the Netherlands CardioVascular Research Initiative: “the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences” (CVON2017-2020; Acronym Genius2 to P.C.N. Rensen, B. van de Sluis, and J.A. Kuivenhoven). J.A. Kuivenhoven is Established Investigator of the Netherlands Heart Foundation (2015T068). The Research Fund at Rigshospitalet, Copenhagen University Hospital, a grant from the Odd Fellow Order, the 2018 Anitschkow Award from the European Atherosclerosis Society, and Kirsten and Freddy Johansen’s Award 2018. B. Cariou and A. Rimbert were supported by the French national project CHOPIN (CHolesterol Personalized INnovation) funded by the Agence Nationale de la Recherche (ANR-16-RHUS-0007) and coordinated by the CHU of Nantes, a grant from the Fondation de France (grant No. 2015-00047967) and the GENESIS project, funded by the Agence Nationale de la Recherche (ANR-21- CE14-0051). A.R. is supported by a post-doctoral fellowship grant from the “Fondation Recherche Médicale.”
Publisher Copyright:
© 2022 Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
PY - 2022/10
Y1 - 2022/10
N2 - BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.METHODS: Common and rare genetic variants in the
GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare
GPR146 variants.
RESULTS: In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (
P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between
GPR146 gene expression and plasma lipid and liver enzyme levels.
CONCLUSIONS: This study shows that carriers of new genetic
GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.
AB - BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.METHODS: Common and rare genetic variants in the
GPR146 gene locus were used as research instruments in the UK Biobank. The Lifelines, The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare
GPR146 variants.
RESULTS: In the UK Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (
P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between
GPR146 gene expression and plasma lipid and liver enzyme levels.
CONCLUSIONS: This study shows that carriers of new genetic
GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans.
KW - G-protein-coupled receptor
KW - cardiovascular diseases
KW - dyslipidemia
KW - human genetics
KW - metabolic diseases
UR - https://www.scopus.com/pages/publications/85138459558
U2 - 10.1161/ATVBAHA.122.317514
DO - 10.1161/ATVBAHA.122.317514
M3 - Article
C2 - 36047410
SN - 1079-5642
VL - 42
SP - 1262
EP - 1271
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 10
ER -