Cytokine Gene Polymorphism and Cancer Risk: A Promising Tool for Individual Susceptibility and Prognostic Implications

Cytokines are potent molecules produced mainly by specific activated immune cells to control inflammatory responses besides other biologic processes. Although active participation of cytokines provides defense against carcinogenesis on the other hand, deregulation at the genetic level influences their activity to promote tumor development. Among many aspects, constitutional polymorphic sequence variations are key factors that derange the cytokine expression to lead an individual’s propensity to risk for different cancers. Cytokine polymorphisms are now believed to alter these critical molecules that have a dual face in carcinogenesis as, when implicated in the activation of the immune response, these molecules check the cancer development while their persistent inflammatory reaction can envisage the development of malignancy and tumor growth. We have given ample evidence of case-control studies in a range of cancers where substantial evidence, as reported in this chapter, links polymorphism of cytokine gene susceptibility with numerous cancers. Cytokine gene polymorphism is vital to be significant bimolecular genetic determinants of susceptibility and prognosis of cancer. A strong need is felt for more case-control association studies in cytokine candidate genes involved in specific pathways for particular cancer in bigger powered sample sizes involving additional variables to disclose their factual risk for cancer.

Association of Helicobacter pylori Infection and Host Cytokine Gene Polymorphism with Gastric Cancer

The global cancer burden of new cases of various types rose with millions of death in 2018. Based on the data extracted by GLOBOCAN 2018, gastric cancer (GC) is the third leading cause of mortality related to cancer across the globe. Carcinogenic or oncogenic infections associated with Helicobacter pylori (Hp) are regarded as one of the essential risk factors for GC development. It contributes to the increased production of cytokines that cause inflammation prior to their growth in the host cells. Hp infections and specific types of polymorphisms within the host cells encoding cytokines are significant contributors to the hostʼs increased susceptibility in terms of the development of GC. Against the backdrop of such an observation is that only a small portion of the cells infected can become malignant. The diversities are a consequence of the differences in the pathogenic pathway of the Hp, susceptibility of the host, environmental conditions, and interplay between these factors. It is evident that hosts carrying cytokine genes with high inflammatory levels and polymorphism tend to exhibit an increased risk of development of GC, with special emphasis being placed on the host cytokines gene polymorphisms.

The Association of Cytokine Genes Polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) in Type 2 Diabetes Mellitus-tuberculosis

BACKGROUND: The cytokine gene polymorphism is associated with the development of metabolic disorder conditions and infectious diseases such as Type 2 diabetes mellitus (T2DM) and tuberculosis (TB) disease. AIM: The objective of the study is an attempt to examine the association of cytokine genes polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) in T2DM-TB patients. METHODS: The cytokine genes polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) were investigated in 46 T2DM-TB patients, 46 T2DM patients, and 46 healthy controls. Cytokine genes polymorphism was carried out by the polymerase chain reaction-restriction fragment length polymorphism. Odds ratio (OR) with 95% confidence interval (CI) and p-value was calculated to determine the association between cytokine genes polymorphisms as the risk factor to T2DM-TB development. RESULTS: No association between genotypes and alleles of cytokine genes polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) in T2DM-TB compared to control group (p = 0.434; OR = 0.373; 95% CI = 0.068-2.028 and p = 0.444; OR = 0.387; 95% CI = 0.073–2.046), (p = 0.833; OR = 0.915; 95% CI = 0.400–2.092 and p = 0.864; OR = 1.061; 95% CI = 0.541–2.078), and (p = 0.815; OR = 0.896; 95% CI = 0.357–2.246 and p = 0.882; OR = 0.957; 95% CI = 0.534–1.715). This study also found no association between genotypes and alleles of cytokine genes polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) with T2DM-TB compared to T2DM group (p = 1; OR = 0.652; 95% CI = 0.104–4.094 and p = 1; OR = 0.659; 95% CI = 0.108–4.041), (p = 0.189; OR = 1.786; 95% CI = 0.749–4.262 and p = 0.098; OR = 1.857; 95% CI = 0.887–3.889), and (p = 0.374; OR = 1.488; 95% CI = 0619–3.579 and p = 0.365; OR = 1.316; 95% CI=0.727–2.382). CONCLUSION: There is no association of the cytokine genes polymorphisms (IL1β+3954 C/T, IL18-137 G/C, and IL18-607 C/A) in T2DM-TB compared to control and T2DM groups, and all cytokine genes polymorphisms not as the risk factor to T2DM-TB development in this population.

Frequency of Cytokine Gene Polymorphism in Full-Term Newborns with Hypoxic Events

Background. An infant brain damage is an extremely urgent problem, this pathology is difficult to prevent, and subsequently it manifests itself with a variety of neurological consequences. Various mechanisms are involved in neurodamage; cytokines, as well as genes that control their activity, are under a great concern today. However, there is little data about their role as predictors of the brain damage among children after hypoxia. Aim of the research. To identify the frequency of cytokine gene polymorphism: interleukin (IL)-1β(C-511T), IL-1β(C3953T), IL-4(C589T), IL-6(C174G), IL-10(C819T), IL-10(G1082A) among newborns with hypoxic events. Materials and methods. The study involved 128 full-term newborn patients with hypoxic events: the first group (n = 48) included newborns who experienced chronic intrauterine hypoxia (CVH), the second group (n = 80) included newborns born in asphyxiation. Control group (52) included babies born without asphyxia and not suffering from CVH. A retrospective analysis of case-records was carried out. The material for molecular genetic analysis was DNA samples isolated from umbilical cord blood leukocytes using DNA Express Blood reagents (Scientific and Production Company LITECH, Moscow). Results. Compared to the control group (p = 0.03) children born in asphyxia had their T allele IL-1β (C-511T) prevailed. The group of newborn who had CVH had their TT genotype (p = 0.04) and the T IL-1β allele (C-511T) (p = 0.01) prevailed compared to the control group. In the same study group while studying the polymorphism of the IL-1β gene, the T allele (p = 0.03) at the point C3953T prevailed, in contrast to the control group. Conclusion. Due to the fact that cytokines are part of a reaction cascade leading to the secondary brain damage, under the action of hypoxia, it was found that among newborns undergoing asphyxia and chronic intrauterine hypoxia the increased frequencies of carriage of IL-1β-511TT and IL-1β-3953TT genotypes, and IL-1β-511T and IL-1β-3953T alleles increase the risk of neurodamage.

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.