Academic Journal
Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile
| العنوان: | Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile |
|---|---|
| المؤلفون: | Rimbert, A., Yeung, M. W., Dalila, N., Thio, C. H. L., Yu, H., Loaiza, N., Oldoni, F., Graaf, A., van Der, 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., Sluis, B., van De, Snieder, H., Di Filippo, M., Harst, P., van Der, Tybjaerg-Hansen, A., Zimmerman, P., Cariou, B., Kuivenhoven, J. |
| المساهمون: | Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes), ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), University of Groningen Groningen, Universiteit Utrecht / Utrecht University Utrecht, University of Copenhagen = Københavns Universitet (UCPH), National University of Singapore (NUS), University of Texas Southwestern Medical Center Dallas, Leiden University Medical Center (LUMC), Universiteit Leiden = Leiden University, University Medical Center Groningen Groningen (UMCG), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Louis Pradel CHU - HCL, Hospices Civils de Lyon (HCL), Rigshospitalet Copenhagen, Copenhagen University Hospital, NEBION AG Zurich, Switzerland, ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), ANR-21-CE14-0051,GENESIS,GPR146: une nouvelle cible contre les maladies cardiométaboliques(2021) |
| المصدر: | ISSN: 1079-5642. |
| بيانات النشر: | CCSD American Heart Association |
| سنة النشر: | 2022 |
| المجموعة: | Université de Nantes: HAL-UNIV-NANTES |
| مصطلحات موضوعية: | atherosclerosis, liver, allele, mice, phenotype, [SDV]Life Sciences [q-bio] |
| الوصف: | International audience ; 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 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/36047410; PUBMED: 36047410; WOS: 000854289300008 |
| DOI: | 10.1161/atvbaha.122.317514 |
| الاتاحة: | https://inserm.hal.science/inserm-03833180 https://inserm.hal.science/inserm-03833180v1/document https://inserm.hal.science/inserm-03833180v1/file/ATVBAHA.122.317514.pdf https://doi.org/10.1161/atvbaha.122.317514 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.3D72B134 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1161/atvbaha.122.317514 |
|---|