Genetic and functional evidence relates a missense variant in B4GALT1 to lower LDL-C and fibrinogen
Montasser, M. E.; Van Hout, C. V.; McFarland, R.; Rosenberg, A.; Callaway, M.; Shen, B.; Li, N.; Daly, T. J.; Howard, A. D.; Lin, w.; Mao, Y.; Ye, B.; Gatta, G. D.; Tzoneva, G.; Perry, J.; Ryan, K. A.; Miloscio, L.; Economides, A. N.; Regeneron Genetics Center, ; NHLBI TOPMed Program, ; Sztalryd-Woodle, C.; Mitchell, B. D.; Healy, M.; Streeten, E.; Zaghloul, N. A.; Taylor, S. I.; O'Connell, J. R.; Shuldiner, A. R.
Show abstract
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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