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Journal Articles Arteriosclerosis, Thrombosis, and Vascular Biology Year : 2022

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

Ming Yeung
Nawar Dalila
  • Function : Author
Chris H.L. Thio
Haojie Yu
Natalia Loaiza
  • Function : Author
Federico Oldoni
Adriaan van der Graaf
Siqi Wang
M. Abdullah Said
Lisanne Blauw
  • Function : Author
Aurore Girardeau
  • Function : Author
Lise Bray
Amandine Caillaud
Vincent Bloks
  • Function : Author
Marie Marrec
  • Function : Author
Philippe Moulin
  • Function : Author
Patrick C.N. Rensen
Bart van de Sluis
Harold Snieder
Mathilde Di Filippo
Pim van der Harst
Anne Tybjaerg-Hansen
  • Function : Author
Philip Zimmerman
  • Function : Author
Bertrand Cariou
Jan Albert Kuivenhoven


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.

Dates and versions

hal-04060057 , version 1 (05-04-2023)



Antoine Rimbert, Ming Yeung, Nawar Dalila, Chris H.L. Thio, Haojie Yu, et al.. Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile. Arteriosclerosis, Thrombosis, and Vascular Biology, 2022, 42 (10), pp.1262-1271. ⟨10.1161/ATVBAHA.122.317514⟩. ⟨hal-04060057⟩
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