Genetic and functional evidence relates a missense variant in B4GALT1 to lower LDL-C and fibrinogen
May E Montasser,
Cristopher V.Van Hout,
Thomas J. Daly,
Alicia D. Howard,
Giusy Della Gatta,
Kathleen A. Ryan,
Aris N Economides,
Regeneron Genetics Center,
NHLBI TOPMed Program,
Braxton D Mitchell,
Norann A Zaghloul,
Simeon I. Taylor,
Jeffrey R O’Connell,
Alan R. Shuldiner
Posted 01 Aug 2019
bioRxiv DOI: 10.1101/721704
Posted 01 Aug 2019
Increased LDL-cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease (CVD). We identified novel associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.5 mg/dl lower LDL-C (p=1.6E-15), and 26 mg/dl lower plasma fibrinogen (p= 9.8E-05). N-linked glycan profiling found p.Asn352Ser to be associated (p-values from 1.4E-06 to 1.0E-17) with decreased glycosylation of glycoproteins including: fibrinogen, ApoB100, immunoglobulin G (IgG), and transferrin. In vitro assays found that the mutant (352Ser) protein had 50% lower galactosyltransferase activity compared to wild type (352Asn) protein. Knockdown of b4galt1 in zebrafish embryos resulted in significantly lower LDL-C compared to control, which was fully rescued by co-expression of 352Asn human B4GALT1 mRNA but only partially rescued by co-expression of 352Ser human B4GALT1 mRNA. Our findings establish B4GALT1 as a novel gene associated with lower LDL-C and fibrinogen and suggest that targeted modulation of protein glycosylation may represent a therapeutic approach to decrease CVD risk.
- Downloaded 548 times
- Download rankings, all-time:
- Site-wide: 54,269
- In genetics: 2,411
- Year to date:
- Site-wide: 43,568
- Since beginning of last month:
- Site-wide: 36,222
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!