Abstract
Objective Elucidating the genetic basis underlying hepatic hemostatic gene expression variability
may contribute to unraveling genetic factors contributing to thrombotic or bleeding
disorders. We aimed to identify novel cis-regulatory variants involved in regulating hemostatic genes by analyzing allele-specific
expression (ASE) in human liver samples.
Study Design Biopsies of human liver tissue and blood were collected from adults undergoing liver
surgery at the Sahlgrenska University Hospital (n = 20). Genomic deoxyribonucleic acid (gDNA) and total ribonucleic acid (RNA) were
isolated. A targeted approach was used to enrich and sequence 35 hemostatic genes
for single nucleotide polymorphism (SNP) analysis (gDNAseq) and construct individualized
genomes for transcript alignment. The allelic ratio of transcripts from targeted RNAseq
was determined via ASE analysis. Public expression quantitative trait loci (eQTL)
and genome-wide association study (GWAS) data were used to assess novelty and importance
of the ASE SNPs (and proxies, r
2 ≥ 0.8) for relevant traits/diseases.
Results Sixty percent of the genes studied showed allelic imbalance across 53 SNPs. Of these,
7 SNPs were previously validated in liver eQTL studies. For 32 with eQTLs in other
cell/tissue types, this is the first time genotype-specific expression is demonstrated
in liver, and for 14 ASE SNPs, this is the first ever reported genotype–expression
association. A total of 29 ASE SNPs were previously associated with the respective
plasma protein levels and 17 ASE SNPs to other relevant GWAS traits including venous
thromboembolism, coronary artery disease, and stroke.
Conclusion Our study provides a comprehensive ASE analysis of hemostatic genes and insights
into the regulation of hemostatic genes in human liver.
Keywords
coagulation factors - gene regulation - hemostasis - single nucleotide polymorphisms
- thrombosis
