Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity

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，von Willebrand Factor）广泛存在双天线核心岩藻糖基化聚糖修饰。VWF表面的绝大多数N-连接聚糖与O-连接聚糖均发生唾液酸化修饰。凝血因子VIII（FVIII，Factor VIII）同样存在糖基化修饰，其聚糖结构与VWF高度相似。ST3GAL家族唾液酸转移酶（ST3GAL sialyltransferases）可催化唾液酸以α2,3位糖苷键连接方式，结合至N-连接及O-连接聚糖的末端。该唾液酸化修饰对于VWF的合成与生物学活性至关重要。本研究基于动脉粥样硬化风险社区（Atherosclerosis Risk in Communities, ARIC）研究的遗传与表型数据，分析了ST3GAL4基因的单核苷酸多态性（SNPs，single nucleotide polymorphisms）与12117名受试者血浆VWF水平及FVIII活性的相关性。同时，本研究还分析了1000基因组（1000 Genomes, 1000G）项目中26个族群的2535名受试者的ST3GAL4 SNPs，以开展族群多样性评估、SNP填充分析及ST3GAL4单倍型分析。研究分别在ARIC全基因组关联研究（GWAS）数据库与1000G数据库中鉴定出14个及1714个ST3GAL4遗传变异体，其中46%的变异体在等位基因频率上呈现显著族群多样性。在ARIC GWAS鉴定出的14个ST3GAL4 SNPs中，内含子区域的rs2186717、rs7928391及rs11220465经校正年龄、体质量指数、高血压、糖尿病、吸烟史及ABO血型因素后，与血浆VWF水平及FVIII活性显著相关。本研究彰显了下一代测序在新型遗传变异发现中的应用价值，同时揭示了ST3GAL4基因存在显著的族群多样性。我们还探讨了这些内含子SNPs调控ST3GAL4生物合成，进而影响VWF与FVIII活性的潜在分子机制。