Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Regeneron Genetics Center, LLC, Tarrytown, NY 10591, USA.
Science. 2021 Dec 3;374(6572):1221-1227. doi: 10.1126/science.abe0348. Epub 2021 Dec 2.
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 () and 13.9 milligrams per deciliter lower LDL-C ( = 4.1 × 10) and 29 milligrams per deciliter lower plasma fibrinogen ( = 1.3 × 10). gene–based analysis in 544,955 subjects showed an association with decreased coronary artery disease (odds ratio = 0.64, = 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. Ser 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.
血液中低密度脂蛋白胆固醇（LDL-C）和纤维蛋白原水平升高是心血管疾病的独立危险因素。我们发现，β-1,4-半乳糖基转移酶 1 （）中一个功能域的丰富错义变异（p.Asn352Ser）与 LDL-C 降低 13.9 毫克/分升（= 4.1×10）和血浆纤维蛋白原降低 29 毫克/分升（= 1.3×10）有关。在 544,955 名受试者中进行的基于基因的分析显示，与降低的冠状动脉疾病（比值比= 0.64，= 0.006）有关。与野生型蛋白相比，突变蛋白的半乳糖基转移酶活性降低了 50%。对人血清中的 N-连接糖基化谱分析发现，丝氨酸 352 等位基因与载脂蛋白 B100、纤维蛋白原、免疫球蛋白 G 和转铁蛋白的半乳糖化和唾液酸化减少有关。Ser 敲入小鼠显示 LDL-C 和纤维蛋白原降低。我们的研究结果表明，靶向调节蛋白质半乳糖化可能代表一种降低心血管疾病的治疗方法。
