title: Association of Single Nucleotide Polymorphisms in the ST3GAL4 Gene with VWF Antigen and Factor VIII Activity.
abstract: 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.
authors: BloodWorks Northwest Research Institute, Seattle, WA, United States of America.|Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Jaewoo
authors: J
authors: Song
authors: Human Genome Sequencing Center, Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, 77030, United States of America.
authors: Cheng
authors: C
authors: Xue
authors: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America.
authors: John S
authors: JS
authors: Preisser
authors: BloodWorks Northwest Research Institute, Seattle, WA, United States of America.
authors: Drake W
authors: DW
authors: Cramer
authors: BloodWorks Northwest Research Institute, Seattle, WA, United States of America.
authors: Katie L
authors: KL
authors: Houck
authors: Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu, China.
authors: Guo
authors: G
authors: Liu
authors: Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors: Aaron R
authors: AR
authors: Folsom
authors: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America.
authors: David
authors: D
authors: Couper
authors: Human Genome Sequencing Center, Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, 77030, United States of America.|Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
authors: Fuli
authors: F
authors: Yu
authors: BloodWorks Northwest Research Institute, Seattle, WA, United States of America.|Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States of America.
authors: Jing-Fei
authors: JF
authors: Dong
mesh_terms: D005169:Factor VIII / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012799:Sialyltransferases / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human