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.

doi:10.1101/721704

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bioRxiv · 10.1101/721704

Genetic and functional evidence relates a missense variant in B4GALT1 to lower LDL-C and fibrinogen

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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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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.. 2019-08-01. Genetic and functional evidence relates a missense variant in B4GALT1 to lower LDL-C and fibrinogen. https://doi.org/10.1101/721704

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