| dc.contributor.advisor | Mansur, Ashham Prof. Dr. | |
| dc.contributor.author | Mewes, Caspar Niclas | |
| dc.date.accessioned | 2021-08-19T10:15:14Z | |
| dc.date.available | 2021-09-01T00:50:03Z | |
| dc.date.issued | 2021-08-19 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0008-58E7-1 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8784 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8784 | |
| dc.language.iso | deu | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | de |
| dc.title | Einfluss genetischer Varianten aus dem CTLA-4-Gen auf den Krankheitsverlauf von Patienten mit Sepsis | de |
| dc.type | doctoralThesis | de |
| dc.title.translated | Impact of CTLA-4 genetic variants on the course of disease in patients with sepsis | de |
| dc.contributor.referee | Mansur, Ashham Prof. Dr. | |
| dc.date.examination | 2021-08-25 | |
| dc.description.abstracteng | BACKGROUND: The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is co-inhibitory immune checkpoint protein on the surface of T-cells. It transmits an inhibitory signal in the process of T-cell mediated immune response and thereby downregulates host immune reaction preventing an overreaction of the immune system. Functional genetic variants from the CTLA-4 gene have been reported to associate with an enhanced T-cell activation and proliferation as well as an increased susceptibility to autoimmune diseases.
The present study aimed to investigate the effect of the CTLA-4 rs733618, rs231775 and rs3087243 single nucleotide polymorphisms (SNPs) as well as inferred haplotypes on the mortality in patients with sepsis.
METHODS: 644 adult patients with sepsis were prospectively enrolled from three surgical intensive care units of the University Medical Center Goettingen since February 2012. Blood for genotyping was drawn within 72 hours after sepsis onset and 28 and 90-day mortality were recorded. DNA was extracted and all patients were successfully genotyped using predesigned genotyping assays.
RESULTS: Kaplan-Meier survival analysis was performed and revealed a significantly lower 28-day mortality for CTLA-4 rs231775 GG-homozygotes (n = 101) compared to A-allele carriers (n = 543; 11.9% vs. 21.5%, p = 0.0308) as well as 90-day mortality (21.8% vs. 31.9%, p = 0.0357). CTLA-4 rs3087243 G-allele carriers (n = 502) also showed a favorable 28-day mortality (17.9% vs. 27.5%, p = 0.0161) and 90-day mortality (27.3% vs. 40.8%, p = 0.0024) compared to AA-homozygous patients (n = 142) at this position. Furthermore, CTLA-4 TAA-haplotype-negative patients (compound of CTLA 4 rs733618 T-, rs231775 A- and rs3087243 A-allele, n = 197) presented a significantly better 28-day mortality (14.7% vs. 22.4%, p = 0.0271) as well as 90-day mortality (24.4% vs. 32.9%, p = 0.0265) compared to TAA-haplotype carriers (n = 447).
Carrying the CTLA-4 rs231775 GG genotype, rs3087243 G-allele and not carrying the TAA haplotype were found to be significant independent prognostic variables for either 28- or 90-day survival after adjusting for potential confounders in the multivariate Cox regression analysis.
CONCLUSION: This study is the first to identify the prognostic relevance of genetic variants from the CTLA-4 gene for the survival of patients with sepsis. The findings may be helpful for the identification of high-risk patients, further understanding of the pathophysiology of sepsis and for the potential evaluation of personalized therapy approaches for septic patients, i.e. using anti-CTLA-4 antibodies. | de |
| dc.contributor.coReferee | Dressel, Ralf Prof. Dr. | |
| dc.contributor.thirdReferee | Grade, Marian PD Dr. | |
| dc.subject.eng | Sepsis, CTLA-4 | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0008-58E7-1-9 | |
| dc.affiliation.institute | Medizinische Fakultät | de |
| dc.subject.gokfull | Anästhesiologie / Intensivmedizin / Notfallmedizin / Analgesie - Allgemein- und Gesamtdarstellungen (PPN619875917) | de |
| dc.description.embargoed | 2021-09-01 | |
| dc.identifier.ppn | 1767498802 | |