美国马里兰大学医学院May E. Montasser研究团队在研究中取得进展。他们用遗传和功能证据表明B4GALT1的错义突变与低密度脂蛋白和纤维蛋白原有关。这一研究成果于2021年12月3日发表在国际学术期刊《科学》上。
研究人员确定了β-1,4-半乳糖基转移酶1(B4GALT1) 功能域中富含的Amish错义变体 (p.Asn352Ser) 与每分升13.9毫克低LDL-C(P = 4.1 × 10–19)和血浆纤维蛋白原降低29毫克/分升(P = 1.3 × 10–5)的关系。对544,955名受试者进行的基于B4GALT1基因分析表明其与冠状动脉疾病减少相关（优势比=0.64，P=0.006）。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N联聚糖分析发现丝氨酸352等位基因与载脂蛋白B100、纤维蛋白原、免疫球蛋白G、转铁蛋白的半乳糖基化以及唾液酸化降低有关。B4galt1 353Ser敲入小鼠显示出LDL-C和纤维蛋白原降低。该研究结果表明，蛋白质半乳糖基化的靶向调节可能是一种针对心血管疾病的治疗方法。
据了解，低密度脂蛋白胆固醇 (LDL-C) 和纤维蛋白原的血液水平升高是与心血管疾病发生有关的独立危险因素。
附：英文原文
Title: Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen
Author: 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
Issue&Volume: 2021-12-03
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.
DOI: abe0348
Source: https://www.science.org/doi/10.1126/science.abe0348