Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

Antoine Rimbert*, Ming W Yeung, Nawar Dalila, Chris H L Thio, Haojie Yu, Natalia Loaiza, Federico Oldoni, Adriaan van der Graaf, Siqi Wang, M Abdullah Said, Lisanne L Blauw, Aurore Girardeau, Lise Bray, Amandine Caillaud, Vincent W Bloks, Marie Marrec, Philippe Mouli, Patrick C N Rensen, Bart van de Sluis, Harold SniederMathilde Di Filippo, Pim van der Harst, Anne Tybjaerg-Hansen, Philippe Zimmerman, Bertrand Cariou, Jan Kuivenhoven

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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, and 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.

Original languageEnglish
Pages (from-to)1262-1271
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number10
Early online date1-Sept-2022
Publication statusPublished - Oct-2022

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