Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen

Disease areas:

• heart and blood vessels

Last updated:

2 July 2025

Author(s):

May E. Montasser, Cristopher V. Van Hout, Lawrence Miloscio, Alicia D. Howard, Avraham Rosenberg, Myrasol Callaway, Biao Shen, Ning Li, Adam E. Locke, Niek Verweij, Tanima De, Manuel A. Ferreira, Luca A. Lotta, Aris Baras, Thomas J. Daly, Suzanne A. Hartford, Wei Lin, Yuan Mao, Bin Ye, Derek White, Guochun Gong, James A. Perry, Kathleen A. Ryan, Qing Fang, Gannie Tzoneva, Evangelos Pefanis, Charleen Hunt, Yajun Tang, Lynn Lee, Regeneron Genetics Center Collaboration‡, Carole Sztalryd-Woodle, Braxton D. Mitchell, Matthew Healy, Elizabeth A. Streeten, Simeon I. Taylor, Jeffrey R. O'Connell, Aris N. Economides, Giusy Della Gatta, Alan R. Shuldiner

Publish date:

2 December 2021

Journal:

Science

PubMed ID:

34855475

DOI:

10.1126/science.abe0348

Abstract

Increased blood levels of low-density lipoprotein cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease. We identified associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.9 milligrams per deciliter lower LDL-C (P = 4.1 × 10^-19) and 29 milligrams per deciliter lower plasma fibrinogen (P = 1.3 × 10^-5). B4GALT1 gene-based analysis in 544,955 subjects showed an association with decreased coronary artery disease (odds ratio = 0.64, P = 0.006). The mutant protein had 50% lower galactosyltransferase activity compared with the wild-type protein. N-linked glycan profiling of human serum found serine 352 allele to be associated with decreased galactosylation and sialylation of apolipoprotein B100, fibrinogen, immunoglobulin G, and transferrin. B4galt1 ³⁵³Ser knock-in mice showed decreases in LDL-C and fibrinogen. Our findings suggest that targeted modulation of protein galactosylation may represent a therapeutic approach to decreasing cardiovascular disease.