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University Medical Center Groningen

New Key Publication: Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

01 September 2022

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.

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