New Key Publication: Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile
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 GPR146gene 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
- 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 Snieder
- Mathilde Di Filippo
- Pim van der Harst
- Anne Tybjaerg-Hansen
- Philippe Zimmerman
- Bertrand Cariou
- Jan Kuivenhoven
More Information: Arterioscler Thromb Vasc Biol 2022 Sep 1;101161ATVBAHA122317514. doi: 10.1161/ATVBAHA.122.317514. [Pubmed]
Last modified: | 05 September 2022 09.49 a.m. |
More news
-
10 June 2024
Swarming around a skyscraper
Every two weeks, UG Makers puts the spotlight on a researcher who has created something tangible, ranging from homemade measuring equipment for academic research to small or larger products that can change our daily lives. That is how UG...
-
21 May 2024
Results of 2024 University elections
The votes have been counted and the results of the University elections are in!