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.
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