The Positivity Rate of IA-2A and ZnT8A in the Chinese Han Population With Type 1 Diabetes Mellitus: Association With rs1143627 and rs1143643 Polymorphisms in the IL1B Gene

Objective: To investigate the association between susceptibility to type 1 diabetes mellitus (T1DM) and polymorphisms (rs1143627 and rs1143643) in the interleukin 1 beta (IL1B) gene in the Chinese Han population.Methods: The Meso Scale Discovery (MSD) method was used to detect the concentration of IL-1β in 24 T1DM patients and 27 healthy controls. MassARRAY was used to analyze the polymorphisms in the IL1B gene in 510 patients with classic T1DM and 531 healthy controls. The general data of the T1DM patients and healthy controls were compared by the chi-square test and Mann-Whitney U test. The chi-square test and logistic regression were used to analyze the frequency distributions of alleles and genotypes of polymorphisms in the IL1B gene. The Kruskal-Wallis H test and chi-square test were used for the genotype-phenotype analysis of rs1143627 and rs1143643 in the IL1B gene.Results: ① The concentration of IL-1β in T1DM patients was significantly higher than that in healthy controls. ② rs1143627 and rs1143643 in the IL1B gene were significantly correlated with the positivity rates for IA-2A and ZnT8A; genotype GG at rs1143627 and genotype CC at rs1143643 in the case group showed lower positivity rates for IA-2A and ZnT8A. ③ There was no significant difference in the genotypes or allele frequencies at rs1143627 (GG/GA/AA) or rs1143643 (CC/CT/TT) between the case group and control group (p > 0.05). ④ rs1143627 and rs1143643 were not found to be linked to T1DM susceptibility under different genetic models.Conclusion: rs1143627 and rs1143643 in the IL1B gene correlate with the positivity rate of IA-2A and ZnT8A in Chinese Han individuals with T1DM.

Polymorphism of Interleukin-1 Gene Cluster in Polish Patients with Acute Coronary Syndrome

Background and objectives: Some experimental studies demonstrated adverse modulation of atherothrombosis by interleukin-1beta (IL-1b). To assess the relationship between the five most common variants of three polymorphisms of the IL1b gene cluster and the complexity of coronary atherosclerosis expressed in Gensini Score (GS), and the age of onset of the first acute coronary syndrome (ACS), we assessed the patients (pts) hospitalized due to ACS in this aspect. Materials and Methods: 250 individuals were included. The single nucleotide polymorphisms of IL1b gene: transition T/C at -31 position, C/T at -511, and those of IL1 receptor antagonist gene (IL1RN)—variable number of tandem repeats allele 1, 2, 3, or 4—were determined by PCR. GS was calculated from the coronary angiogram performed at the index ACS. The impact of the presence of T or C and allele 1 to 4 at the investigated loci on the mean GS, GS greater than 40, mean age of onset of ACS, and the fraction of pts over 60 years of age at ACS were compared between the five most common genotype variants. Results: The five most common variants were present in 203 pts (81.2%). Patients with pair 22 in ILRN had the lowest rate and those with pair 12 had the highest rate of ACS before 60 years of age (29.4 vs. 67.8%; p = 0.004). GS > 40 entailed an eight-fold increase of risk, as observed when pts with one T allele at locus -31 were compared with carriers of 2 or no T allele at this locus: OR 8.73 [CI95 4.26–70.99] p = 0.04. Conclusion: Interleukin-1 beta is subject to frequent genetic variability and our results show a potential relationship of this polymorphism with the extent of coronary atherosclerosis and age at the first ACS.

Signaling Through Purinergic Receptor P2Y2 Enhances Macrophage IL-1β Production

The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 inflammasome is activated in murine resident peritoneal macrophages. Deficiency or pharmacological inhibition of the purinergic receptor P2Y2 reverted the increase of IL-1β release induced by nucleotides. IL-1β increase was found dependent on the expression of Il1b gene and probably involving JNK activity. On the contrary, nucleotides decreased the production of a different proinflammatory cytokines such as TNF-α. These results suggest that nucleotides could shape the response of macrophages to obtain a unique proinflammatory signature that might be relevant in unrevealing specific inflammatory conditions.

Cytokine gene polymorphism as a factor of predisposition to development of chronic purulent otitis media

В последние десятилетия распространенность хронического гнойного среднего отита (ХГСО) заметно выросла. Значительная роль при воспалении, в том числе в патогенезе ХГСО, отводится клеточным медиаторам - цитокинам. Доказана роль полиморфизма генов цитокинов в развитии заболеваний, ассоциированных с воспалительными процессами. Цель работы - проанализировать взаимосвязь полиморфизма генов IL1В (С3953Т, С511Т, Т31С), IL10 (G1082A, C592A, C819T), IL6 (С174G) и TNFА (G308A) с развитием ХГСО и возрастным фактором начальных его проявлений. Методика. Распределение генотипов аллельных вариантов генов цитокинов (IL-1, IL-6, IL-10 и TNF-α) анализировали у 299 пациентов с ХГСО в зависимости от сроков начала заболевания (в возрасте до 14 лет, от 15 до 30 лет, старше 30 лет). Контрольную группу составили 183 здоровых добровольца с сопоставимым распределением по полу и возрасту. Для определения полиморфных вариантов генов IL1В (-3953, -511, -31), IL10 (-1082, -592, -819), IL6 (-174) и TNFА (-308) применяли метод ПЦР в режиме реального времени. Об ассоциации генотипов с заболеванием судили по величине отношения шансов (Odds Ratio (OR)) и коэффициентов Юла (Q) и контингенции (Фи, Φ). За критический уровень значимости при проверке статистических гипотез принимался p≤0,05. Результаты. Выявлено, что к развитию ХГСО предрасполагают полиморфные варианты генов цитокинов IL1В, IL10 и TNFА. Наиболее значимыми в формировании предрасположенности к развитию заболевания являются генотипы С/С полиморфизмов С3953Т и Т31С гена IL1В, А/А полиморфизма G1082A и Т/Т полиморфизма С819Т гена IL10. Полиморфные варианты генов IL1В (генотип C/C полиморфизмов С3953Т и Т511С) и IL10 (генотип А/A полиморфизма G1082A) сочетаются с дебютом ХГСО в возрасте до 14 лет. Полиморфизм C174G гена IL6 не оказывает предрасполагающего влияния на развитие болезни. Протективный эффект в отношении развития ХГСО связан с носительством гомозиготного генотипа Т/Т полиморфизмов С511Т и Т31С гена IL1В и гомозиготного генотипа G/G полиморфизма G1082A гена IL10. Заключение. К развитию ХГСО предрасполагают полиморфизмы генов про- и противовоспалительных цитокинов, дисбаланс которых обусловливает патологическое течение иммунного ответа и раннюю (в детском возрасте) клиническую манифестацию болезни. In recent decades, prevalence of chronic purulent otitis media has increased markedly. A significant role in inflammation, including the pathogenesis of chronic purulent otitis media, is assigned to the cellular mediators, cytokines. The predisposing role of cytokine gene polymorphism in development of inflammatory-associated diseases has been proven. Aim. To analyze the relationship of IL1B (C3953T, C511T, T31C), IL10 (G1082A, C592A, C819T), IL6 (C174G), and TNFA (G308A) gene polymorphisms with development of chronic purulent otitis media and the age of its primary manifestation. Methods. Distribution of genotypes of allelic variants in cytokine (IL-1, IL-6, IL-10 and TNF-α) genes was analyzed in 299 patients (129 men and 170 women aged 38.0 ± 4.3) based on the age of disease onset (with chronic purulent otitis media diagnosed at age of 14, from 15 to 30, and older than 30). The control group consisted of 183 sex- and age matched healthy volunteers. Genomic DNA was isolated from whole blood leukocytes. Real-time PCR was used for determination of polymorphic variants in IL1B (-3953, -511, -31), IL10 (-1082, -592, -819), IL6 (-174), and TNFA (-308) genes. The association of genotypes with the disease was evaluated by the odds ratio (OR) and the values of Yule (Q) and contingent (Phi, Φ) coefficients. The critical significance level for the statistical hypotheses tests was taken as <0.05. Results. IL1B, IL10, and TNFA cytokine gene polymorphisms predisposed to development of chronic purulent otitis media. The genotypes C/C of C3953T and T31C polymorphisms in the IL1B gene, A/A of G1082A polymorphism, and T/T of C819T polymorphism in the IL10 gene are the most significant ones in the predisposition to disease development. Polymorphic variants of IL1B (C/C genotype of C3953T and T511C polymorphisms) and IL10 (A/A genotype of G1082A polymorphism) genes are associated with the onset of chronic purulent otitis media at age of 14. The C174G polymorphism in the IL6 gene does not predispose to the disease. Protection from the development of chronic purulent otitis media is associated with carriage of the T/T homozygous genotype of C511T and T31C polymorphisms in the IL1B gene and the G/G homozygous genotype of G1082A polymorphism in the IL10 gene. Conclusion. Polymorphisms of pro- and anti-inflammatory cytokine genes predispose to the development of chronic purulent otitis media. An imbalance of these cytokines results in a pathological course of immune response and early (children) clinical manifestation of the disease.