SERPINA1 long transcripts produce non-secretory alpha1-antitrypsin isoform: In vitro translation in living cells

Maslakova, А. А.; Golyshev, Sergey A.; Potashnikova, Daria; Moisenovich, A.M.; Orlovsky, Igor V.; Смирнова, О. В.; Rubtsov, Mikhail A.

doi:10.1016/j.ijbiomac.2023.124433

Cited by 3 publications

(1 citation statement)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another notable gene was SERPINA1. SERPINA regulates immune function and inhibits proteases [65]. The rs28929474 polymorphism near SERPINA1 increases susceptibly to childhood asthma and was previously noted to contribute to the shared genetic relationship between rheumatoid arthritis and osteoporosis [66,67].…”

Section: Genes Of Interestmentioning

confidence: 98%

GlycA and CRP Are Genetically Correlated: Insight into the Genetic Architecture of Inflammageing

Kasher,

Freidin,

Williams

et al. 2024

Biomolecules

View full text Add to dashboard Cite

Inflammageing is a condition of perpetual low-grade inflammation induced by ageing. Inflammageing may be predicted by the C-reactive protein (CRP) or by a recently described biomarker which measures N-glycosylated side chains of the carbohydrate component of several acute-phase proteins known as GlycA. The objective of this study was to examine in depth the genetic relationships between CRP and GlycA as well as between each of them and other selected cytokines, which may shed light on the mechanisms of inflammageing. Using the Olink 96 Inflammation panel, data on inflammatory mediators for 1518 twins from the TwinsUK dataset were acquired. Summary statistics for genome-wide association studies for several cytokines as well as CRP and GlycA were collected from public sources. Extensive genetic correlation analyses, colocalization and genetic enrichment analyses were carried out to detect the shared genetic architecture between GlycA and CRP. Mendelian randomization was carried out to assess potential causal relationships. GlycA predicted examined cytokines with a magnitude twice as great as that of CRP. GlycA and CRP were significantly genetically correlated (Rg = 0.4397 ± 0.0854, p-value = 2.60 × 10−7). No evidence of a causal relationship between GlycA and CRP, or between these two biomarkers and the cytokines assessed was obtained. However, the aforementioned relationships were explained well by horizontal pleiotropy. Five exonic genetic variants annotated to five genes explain the shared genetic architecture observed between GlycA and CRP: IL6R, GCKR, MLXIPL, SERPINA1, and MAP1A. GlycA and CRP possess a shared genetic architecture, but the relationship between them appears to be modest, which may imply the promotion of differing inflammatory pathways. GlycA appears to be a more robust predictor of cytokines compared to CRP.

show abstract

Section: Genes Of Interestmentioning

confidence: 98%

GlycA and CRP Are Genetically Correlated: Insight into the Genetic Architecture of Inflammageing

Kasher,

Freidin,

Williams

et al. 2024

Biomolecules

View full text Add to dashboard Cite

show abstract

Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression

Jiamutai,

Hatfield,

Herbert

et al. 2024

Preprint

View full text Add to dashboard Cite

Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. TheSERPINA1mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide.SERPINA1is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels ofSERPINA1mRNA.SERPINA1expression and 3’ end processing were not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data suggest that inflammation influences polyA site choice forSERPINA1transcripts, resulting in reduced A1AT protein expression.

show abstract

Association between inflammatory bowel disease and osteoporosis in European and East Asian populations: exploring causality, mediation by nutritional status, and shared genetic architecture

Kang,

Wu,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

BackgroundWhile previous research has established an association between inflammatory bowel disease (IBD) and osteoporosis (OP), the nature of this association in different populations remains unclear.ObjectiveOur study used linkage disequilibrium scores(LDSC) regression analysis and Mendelian randomization(MR) to assess the genetic correlation and causal relationship between IBD and OP in European and East Asian populations.MethodsWe performed separate genetic correlation and causal analyses for IBD and OP in European and East Asian populations, used the product of coefficients method to estimate the mediating effect of nutritional status on the causal relationship, and used multi-trait analysis to explore the biological mechanisms underlying the IBD-nutrition-OP causal pathway.ResultsOur analysis revealed a significant genetic correlation and causal relationship between IBD and OP in the European population. Conversely, no such correlation or causal relationship was observed in the East Asian population. Mediation analysis revealed a significant mediating effect of nutritional status on the causal pathway between IBD and OP in the European population. Multi-trait analysis of the IBD-nutrition-OP causal pathway identified MFAP2, ATP13A2, SERPINA1, FTO and VCAN as deleterious variants.ConclusionOur findings establish a genetic correlation and causal relationship between IBD and OP in the European population, with nutritional status playing a crucial mediating role.

show abstract

SERPINA1 long transcripts produce non-secretory alpha1-antitrypsin isoform: In vitro translation in living cells

Cited by 3 publications

References 81 publications

GlycA and CRP Are Genetically Correlated: Insight into the Genetic Architecture of Inflammageing

GlycA and CRP Are Genetically Correlated: Insight into the Genetic Architecture of Inflammageing

Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression

Association between inflammatory bowel disease and osteoporosis in European and East Asian populations: exploring causality, mediation by nutritional status, and shared genetic architecture

Contact Info

Product

Resources

About