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 |
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 |
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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>
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