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

Arterioscler Thromb Vasc Biol. 2022 Oct;42(10):1262-1271. doi: 10.1161/ATVBAHA.122.317514. Epub 2022 Sep 1.


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.

Keywords: G-protein-coupled receptor; cardiovascular diseases; dyslipidemia; human genetics; metabolic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins B / genetics
  • Atherosclerosis* / genetics
  • Atherosclerosis* / prevention & control
  • C-Reactive Protein
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Humans
  • Hypobetalipoproteinemias* / genetics
  • Mice
  • Pharmaceutical Preparations
  • Receptors, G-Protein-Coupled / genetics


  • Apolipoproteins B
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Pharmaceutical Preparations
  • Receptors, G-Protein-Coupled
  • C-Reactive Protein