| Title: | Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen |
| Journal: | Science |
| Published: | 2 Dec 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34855475/ |
| DOI: | https://doi.org/10.1126/science.abe0348 |
Publication 10754
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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.</p>
39 Authors
- 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
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