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Identifier 000434660
Title Σακχαρώδης διαβήτης τύπου 2 και ρινική φορεία σε Staphylococcus aureus : γονιδιακοί πολυμορφισμοί και διαμεσολαβητές της μη ειδικής ανοσολογικής απάντησης
Alternative Title Diabetes mellitus type 2 and Staphylococcus aureus nasal carriage:
Author Πλατάκη, Μαρίνα Ν.
Thesis advisor Κοφτερίδης, Διαμαντής
Select a value Σαμώνης, Γεώργιος
Γαλανάκης, Εμμανουήλ
Γουλιέλμος, Γεώργιος
Αγγελάκη, Σοφία
Σχίζα, Σοφία
Φιλιππάτος, Θεοδόσιος
Abstract Objectives: Staphylococcus aureus nasal carriage, an important risk factor for severe infections, is common in patients with type 2 diabetes mellitus (T2D), possibly due to dysregulation of innate immunity. Genetic polymorphisms in host innate immune genes, including interleukin 6 (IL6) and vitamin D receptor (VDR) genes, have been found to be associated with susceptibility to several diseases, including type 2 diabetes (T2D) and various infections. Additionally, vitamin D and cathelicidin (LL-37), a downstream target of vitamin D - VDR complex, are both innate immune markers that play a key role in immunomodulation and may contribute to host defence mechanisms against S. aureus. The aim of this study was to investigate the role of rs1800795 IL6 single nucleotide polymorphism (SNP) on the susceptibility to T2D, as well as to nasal carriage of S. aureus among individuals with T2D. We also examined whether LL-37 serum levels are influenced by the four most common VDR gene polymorphisms [FokI (rs10735810), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236)] in individuals with T2D. Furthermore, we tried to determine the impact of 25- hydroxy vitamin D [25(OH)D] and LL-37 on S. aureus nasal carriage status in T2D patients. Finally, this study aimed to assess the contribution of S. aureus nasal colonization on subsequent staphylococcal infections in diabetic subjects. Patients & methods: The study group consisted of a cohort of 240 T2D patients, followed up at the outpatient clinic of Internal Medicine and Endocrinology Department of University Hospital of Heraklion, during 2013-2014. The control group consisted of 236 healthy age- and sex-matched subjects. All individuals were of self-reported Cretan origin. From all T2D patients, nasal swab was obtained to determine S. aureus nasal colonization by rotating a sterile fiber-tipped swab four times in both anterior nares of each enrolled individual. A repeat swab was obtained, at a one-month interval, for the estimation of persistent carriage status. Diabetic participants were asked about the use of vitamin D supplements. Whole blood was collected from all participants enrolled in the study. One hundred and forty-four patients with T2D and one hundred and eighty healthy controls were genotyped for the IL6 rs1800795 SNP by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). FokI (rs10735810), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) VDR gene polymorphisms had previously been investigated in 173 T2D patients by PCRRFLP. Serum levels of 25(OH)D were estimated in 118 diabetic patients and 94 controls using chemiluminescence immunoassay (CLIA), while serum levels of LL-37 were evaluated in 118 diabetic patients using enzyme-linked immunosorbent assay (ELISA). All T2D patients were followed up for 6 years (2014-2020) and any cases of staphylococcal infections were recorded during this period. Results: S. aureus nasal colonization was found to be at a percentage of 25.8% of T2D patients. Among them, 9.6% were defined as persistent carriers. The G/C genotype and the minor allele C of IL6 rs1800795 SNP analyzed were more common in individuals with T2D than in healthy controls (p=0.004, OR=1.98, 95% CI 1.24-3.18 and p=0.011, OR=1.59, 95% CI 1.11-2.26, respectively). No statistically significant differences have been found between carriers and non-carriers in terms of either allele or genotype frequency. Analyses of subgroups, based on the pattern of carriage (intermittent or permanent), also did not reveal significant differences. T2D patients presented significantly lower 25(OH)D serum levels compared to controls (p<0.001). In particular, 88.6% of T2D patients, whereas only 59.6% of controls, in our study, presented vitamin D deficiency (<20ng/ml) or insufficiency (21-29ng/ml)). No effect of vitamin D daily administration has been found on the rates of S. aureus nasal carriage in T2D patients (p=0.706). T2D patients presented remarkably low serum LL-37 levels (median 0.89, range 0.05-8.62 ng/ml). The presence of the BsmI b allele was related to higher levels of LL-37 (p=0.05), as well as BsmI bb genotype showed higher LL-37 concentratons compared to Bb genotype (p=0.035). TaqI TT homozygotes presented higher LL-37 levels compared to TaqI Tt heterozygotes (p=0.003), as well as the presence of the TaqI T allele was related to a trend of increased levels of LL-37, though not statistically significant (p=0.07). Circulating levels of LL-37 were higher in nasal carriers compared to non-carriers (p<0.001), whereas no difference was observed in 25(OH)D levels. A strong positive correlation was observed between 25(OH)D and LL-37 among non-carriers (r=0.48, p<0.001). This relationship was independent of vitamin D supplementation in a linear regression analysis (p=0.002). Finally, assessing the development of clinical staphylococcal infections in T2D patients during the 6-year follow-up, we found no episodes of bacteremia, while very few episodes of skin and soft tissue infections, caused by S. aureus, were reported. Conclusions: Our study showed that T2D patients present low serum concentrations of vitamin D and LL-37, suggesting defects in innate immunity, which could contribute to higher rates of S. aureus nasal colonization. No impact of vitamin D supplementation on S. aureus nasal colonization has been found in T2D patients. Another finding is that IL6 rs1800795 SNP, although is associated with increased risk for T2D development, might not be associated with higher prevalence of S. aureus nasal carriage in patients with T2D. Our findings, also, suggest that TaqI and BsmI VDR gene polymorphisms are related to serum levels of LL-37, which could be a primary determinant for different S. aureus carriage states in T2D. Finally, we did not prove any significant difference in the frequency of the infections we investigated between S. aureus colonized and non-colonized patients. A weakness of the study is the relatively small number of samples and, therefore, our results need to be confirmed in larger studies.
Language Greek
Subject Cathelicidin
Vitamin D
Βιταμίνη D
Γενετικοί πολυμορφισμοί
Issue date 2020-12-17
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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