Genetic and functional evidence links a missense variant in <i>B4GALT1</i> to lower LDL and fibrinogen

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 (<i>B4GALT1</i>) and 13.9 milligrams per deciliter lower LDL-C (<i>P</i> = 4.1 × 10^–19) and 29 milligrams per deciliter lower plasma fibrinogen (<i>P</i> = 1.3 × 10^–5). <i>B4GALT1</i> gene–based analysis in 544,955 subjects showed an association with decreased coronary artery disease (odds ratio = 0.64, <i>P</i> = 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. <i>B4galt1</i> 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.