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Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile
- Source :
- Rimbert , A , Yeung , M W , Dalila , N , Thio , C H L , Yu , H , Loaiza , N , Oldoni , F , van der Graaf , A , Wang , S , Said , M A , Blauw , L L , Girardeau , A , Bray , L , Caillaud , A , Bloks , V W , Marrec , M , Mouli , P , Rensen , P C N , van de Sluis , B , Snieder , H , Di Filippo , M , van der Harst , P , Tybjaerg-Hansen , A , Zimmerman , P , Cariou , B & Kuivenhoven , J A 2022 , ' Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile ' , Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 42 , no. 10 , pp. 1262-1271 .
- Publication Year :
- 2022
-
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. 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.
Details
- Database :
- OAIster
- Journal :
- Rimbert , A , Yeung , M W , Dalila , N , Thio , C H L , Yu , H , Loaiza , N , Oldoni , F , van der Graaf , A , Wang , S , Said , M A , Blauw , L L , Girardeau , A , Bray , L , Caillaud , A , Bloks , V W , Marrec , M , Mouli , P , Rensen , P C N , van de Sluis , B , Snieder , H , Di Filippo , M , van der Harst , P , Tybjaerg-Hansen , A , Zimmerman , P , Cariou , B & Kuivenhoven , J A 2022 , ' Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile ' , Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 42 , no. 10 , pp. 1262-1271 .
- Notes :
- application/pdf, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1372660796
- Document Type :
- Electronic Resource