Genetic and Epigenetic Association of Hepatocyte Nuclear Factor-1α with Glycosylation in Post-Traumatic Stress Disorder

Abstract

Post-traumatic stress disorder (PTSD) is a complex trauma-related disorder, the etiology and underlying molecular mechanisms of which are still unclear and probably involve different (epi)genetic and environmental factors. Protein N-glycosylation is a common post-translational modification that has been associated with several pathophysiological states, including inflammation and PTSD. Hepatocyte nuclear factor-1α (HNF1A) is a transcriptional regulator of many genes involved in the inflammatory processes, and it has been identified as master regulator of plasma protein glycosylation. The aim of this study was to determine the association between N-glycan levels in plasma and immunoglobulin G, methylation at four CpG positions in the HNF1A gene, HNF1A antisense RNA 1 (HNF1A-AS1), rs7953249 and HNF1A rs735396 polymorphisms in a total of 555 PTSD and control subjects. We found significant association of rs7953249 and rs735396 polymorphisms, as well as HNF1A gene methylation at the CpG3 site, with highly branched, galactosylated and sialyated plasma N-glycans, mostly in patients with PTSD. HNF1A-AS1 rs7953249 polymorphism was also associated with PTSD; however, none of the polymorphisms were associated with HNF1A gene methylation. These results indicate a possible regulatory role of the investigated HNF1A polymorphisms with respect to the abundance of complex plasma N-glycans previously associated with proinflammatory response, which could contribute to the clinical manifestation of PTSD and its comorbidities.

The Association of the Polymorphisms in the FUT8-Related Locus with the Plasma Glycosylation in Post-Traumatic Stress Disorder

“…Although genetic influence on these processes is considered negligible, low heritability N-glycans are often influenced by epigenetic factors, such as changes in DNA methylation [ 62 ]. In particular, recent studies have shown a significant correlation between the methylation of the HNF1A gene and the abundance of the highly sialylated tri- and tetra-antennary N-glycans including the A4G4S4 glycan [ 37 , 38 ]. Since the rs6573604 polymorphism is located within the microRNA 4708 gene ( MIR4708 ), in close proximity of the 5′ end of the FUT8 gene, it is possible that it affects the plasma levels of these N-glycans through molecular epigenetic mechanisms [ 63 ].…”

“…HNF1A is considered a major molecular regulator of fucosylation, possibly by regulating the expression of FUT8 and antennary fucosyltransferases (FUT3, FUT5, FUT6). The genetic and epigenetic associations of the HNF1A gene with levels of several highly branched and sialylated plasma N-glycans, as well as with the core- and antennary-fucosylated IgG N-glycans, were reported in recent studies [ 37 , 38 ]. Numerous single nucleotide polymorphisms (SNPs) were suggested to significantly affect the IgG and plasma N-glycan composition, among which the most prominent ones were located within or near the FUT8 locus and associated with the A2 and A2BG2 glycan levels, as well as with the core-fucosylated FA2G2 and FA3B1G1 N-glycans [ 34 , 35 , 36 ].…”