| Title: | Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile |
| Journal: | Arteriosclerosis Thrombosis and Vascular Biology |
| Published: | 1 Sep 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36047410/ |
| DOI: | https://doi.org/10.1161/atvbaha.122.317514 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.122.317514 |
| Citations: | 4 (4 in last 2 years) as of 8 Aug 2024 |
Publication 12251
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Abstract
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.</p>
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.</p>
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.</p>
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.</p>
26 Authors
- 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 Moulin
- Patrick C.N. Rensen
- Bart van de Sluis
- Harold Snieder
- Mathilde Di Filippo
- Pim van der Harst
- Anne Tybjaerg-Hansen
- Philip Zimmerman
- Bertrand Cariou
- Jan Albert Kuivenhoven
1 Application
| Application ID | Title |
|---|---|
| 15031 | Genetic dissection of cardiovascular risk factors and their relation to disease to establish causality and identify novel targets of therapy |
Enabling scientific discoveries that improve human health