{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:53:40Z","timestamp":1787018020675,"version":"build-2736575974"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T00:00:00Z","timestamp":1664582400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>In mice, GPR146 (G-protein\u2013coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Common and rare genetic variants in the\n                      <jats:italic>GPR146<\/jats:italic>\n                      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\n                      <jats:italic>GPR146<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      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 (\n                      <jats:italic>P<\/jats:italic>\n                      =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\n                      <jats:italic>GPR146<\/jats:italic>\n                      gene expression and plasma lipid and liver enzyme levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      This study shows that carriers of new genetic\n                      <jats:italic>GPR146<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.122.317514","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T05:00:42Z","timestamp":1662008442000},"page":"1262-1271","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Variants in the\n                    <i>GPR146<\/i>\n                    Gene Are Associated With a Favorable Cardiometabolic Risk Profile"],"prefix":"10.1161","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-4926","authenticated-orcid":true,"given":"Antoine","family":"Rimbert","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, France (A.R., A.G., L.B., A.C., M.M., B.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-3109","authenticated-orcid":true,"given":"Ming W.","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.W.Y., S.W., M.S., P.v.d.H.), University Medical Center Groningen, University of Groningen, the Netherlands."},{"name":"Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, the Netherlands (M.W.Y., P.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawar","family":"Dalila","sequence":"additional","affiliation":[{"name":"Section for Molecular Genetics, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.D., A.T.-H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2623-7172","authenticated-orcid":true,"given":"Chris H.L.","family":"Thio","sequence":"additional","affiliation":[{"name":"Department of Epidemiology (C.H.L.T., S.W., H.S.), University Medical Center Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0559-0252","authenticated-orcid":true,"given":"Haojie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (H.Y.)."},{"name":"Precision Medicine Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Loaiza","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section Molecular Genetics (N.L., B.v.d.S., J.A.K.), University Medical Center Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5900-1399","authenticated-orcid":true,"given":"Federico","family":"Oldoni","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (F.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8898-8484","authenticated-orcid":true,"given":"Adriaan","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Department of Genetics (A.v.d.G.), University Medical Center Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4154-2266","authenticated-orcid":true,"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.W.Y., S.W., M.S., P.v.d.H.), University Medical Center Groningen, University of Groningen, the Netherlands."},{"name":"Department of Epidemiology (C.H.L.T., S.W., H.S.), University Medical Center Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2920-7745","authenticated-orcid":true,"given":"M. Abdullah","family":"Said","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.W.Y., S.W., M.S., P.v.d.H.), University Medical Center Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisanne L.","family":"Blauw","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, the Netherlands (L.L.B., P.C.N.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurore","family":"Girardeau","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, France (A.R., A.G., L.B., A.C., M.M., 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