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.

中文翻译：

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遗传和功能证据将 B4GALT1 中的错义变异与降低 LDL 和纤维蛋白原联系起来

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心血管疾病的独立危险因素。我们确定了 β-1,4-半乳糖基转移酶 1 ( B4GALT1 )功能域中富含阿米什人的错义变体 (p.Asn352Ser ) 与降低 13.9 毫克/分升 LDL-C ( P = 4.1 × 10 ^–19 ) 和每分升 29 毫克降低血浆纤维蛋白原 ( P = 1.3 × 10 ^–5 )。544,955 名受试者基于 B4GALT1基因的分析显示与冠状动脉疾病减少有关（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%。人血清的 N-连接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 和转铁蛋白的半乳糖基化和唾液酸化降低有关。B4galt1 ³⁵³ Ser 敲入小鼠显示低密度脂蛋白胆固醇和纤维蛋白原降低。我们的研究结果表明，靶向调节蛋白质半乳糖基化可能代表一种减少心血管疾病的治疗方法。