Song Jaewoo, Xue Cheng, Preisser John S, Cramer Drake W, Houck Katie L, Liu Guo, Folsom Aaron R, Couper David, Yu Fuli, Dong Jing-Fei
BloodWorks Northwest Research Institute, Seattle, WA, United States of America.
Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
PLoS One. 2016 Sep 1;11(9):e0160757. doi: 10.1371/journal.pone.0160757. eCollection 2016.
VWF is extensively glycosylated with biantennary core fucosylated glycans. Most N-linked and O-linked glycans on VWF are sialylated. FVIII is also glycosylated, with a glycan structure similar to that of VWF. ST3GAL sialyltransferases catalyze the transfer of sialic acids in the α2,3 linkage to termini of N- and O-glycans. This sialic acid modification is critical for VWF synthesis and activity. We analyzed genetic and phenotypic data from the Atherosclerosis Risk in Communities (ARIC) study for the association of single nucleotide polymorphisms (SNPs) in the ST3GAL4 gene with plasma VWF levels and FVIII activity in 12,117 subjects. We also analyzed ST3GAL4 SNPs found in 2,535 subjects of 26 ethnicities from the 1000 Genomes (1000G) project for ethnic diversity, SNP imputation, and ST3GAL4 haplotypes. We identified 14 and 1,714 ST3GAL4 variants in the ARIC GWAS and 1000G databases respectively, with 46% being ethnically diverse in their allele frequencies. Among the 14 ST3GAL4 SNPs found in ARIC GWAS, the intronic rs2186717, rs7928391, and rs11220465 were associated with VWF levels and with FVIII activity after adjustment for age, BMI, hypertension, diabetes, ever-smoking status, and ABO. This study illustrates the power of next-generation sequencing in the discovery of new genetic variants and a significant ethnic diversity in the ST3GAL4 gene. We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.
血管性血友病因子（VWF）广泛糖基化，带有双触角核心岩藻糖基化聚糖。VWF上的大多数N-连接和O-连接聚糖都被唾液酸化。凝血因子VIII（FVIII）也被糖基化，其聚糖结构与VWF相似。ST3GAL唾液酸转移酶催化唾液酸以α2,3连接转移至N-聚糖和O-聚糖的末端。这种唾液酸修饰对于VWF的合成和活性至关重要。我们分析了社区动脉粥样硬化风险（ARIC）研究中的遗传和表型数据，以探讨ST3GAL4基因中的单核苷酸多态性（SNP）与12117名受试者血浆VWF水平和FVIII活性之间的关联。我们还分析了来自千人基因组计划（1000G）的26个种族的2535名受试者中发现的ST3GAL4 SNP，以研究种族多样性、SNP填充和ST3GAL4单倍型。我们分别在ARIC全基因组关联研究（GWAS）和1000G数据库中鉴定出14个和1714个ST3GAL4变体，其中46%的等位基因频率存在种族差异。在ARIC GWAS中发现的14个ST3GAL4 SNP中，内含子rs2186717、rs7928391和rs11220465在调整年龄、体重指数、高血压、糖尿病、既往吸烟状况和ABO血型后，与VWF水平和FVIII活性相关。这项研究说明了新一代测序在发现新的遗传变体方面的作用，以及ST3GAL4基因中显著的种族多样性。我们讨论了这些内含子SNP调节ST3GAL4生物合成以及影响VWF和FVIII活性的潜在机制。
