Genotypic and Haplotype Analysis of Interleukin-6 and-18 Gene Polymorphisms in Association with Clinicopathological Factors in Breast Cancer

Background: Cytokines are multifunctional glycoproteins playing a vital role in the tumor microenvironment and in the progression of breast cancer. The immune responses in the tumors restrained by pro- and anti-inflammatory cytokine expressions could be influenced by genetic polymorphisms. Hence, the present study evaluated the contribution of IL6 (rs1800797, rs1800796, and rs1800795), and IL18 (rs1946518, rs187238, and rs549908) genotypes and its haplotypes with risk and progression of breast cancer in south Indian population. Methods: The polymorphisms of IL6 gene -597G>A, -572G>C, -174G>C and IL18 gene -607C>A, -137G>C, and 105A>T were genotyped through PCR-RFLP and As-PCR assays in blood DNA of 600 subjects. We have performed haplotype, LD, univariate, multivariate logistic regression and Kaplan-Meier analyses for the obtained data. Results: The frequency of AA genotype & A-allele of IL6 -597G>A, and CC genotype & C allele of IL6 -174G>C polymorphism was higher in breast cancer patients and was found to be significantly associated with TNM staging, late (advanced) stage, metastasis, etc. While, CG and GG genotypes of IL6 -572 C>G polymorphism had a protective role against breast cancer. Further, IL18 -607C>A, -137G>C & 105A>T polymorphisms were found to be associated with lobular carcinoma subtype, PR-ve and HER2+ve breast cancer patients. Perfect LD was observed between all SNPs of IL6 & IL18 genes under study; G-C-C, A-G-G and A-C-C haplotype combination of IL6 genes had conferred 2.09, 2.25 and 4.72 folds risk for breast cancer respectively. In survival analysis, we observed that the C allele of rs 1800795 was found to be significantly associated with 5years overall survival in breast cancer subjects. Conclusions: Overall, our results suggest the importance of genotypic and haplotype analysis of IL6, and IL18 gene variants in progression and risk identification of breast cancer.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias

Previous reports indicate IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that IL-18 mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared to control (CTR) mice, a "humanized" mouse model of SCD exhibited increased cardiac fibrosis, prolonged action potential duration (APD), higher VT inducibility in vivo, higher cardiac NFκB phosphorylation and circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, translating to reduced outward potassium current (Ito) in isolated cardiomyocytes. IL-18 administration to isolated mice hearts resulted in VTs, originating from the right ventricle, and further reduced Ito in SCD mice cardiomyocytes. Sustained IL-18 inhibition via IL-18 binding protein resulted in decreased cardiac fibrosis and NFκB phosphorylation, improved diastolic function, normalized electrical remodeling and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMC), with QTc strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in non-surviving over surviving subjects. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Role of the polymorphiс variants of immune response and inflammation genes in pathogenesis of ovarian cancer in women of different ethnic origin

Рак яичников (РЯ) занимает одно из лидирующих мест среди онкопатологии репродуктивной сферы у женщин. Высокие показатели заболеваемости и смертности от данного вида рака свидетельствуют о необходимости более глубокого понимания молекулярно-генетических основ заболевания для разработки новых подходов к диагностике и лечению РЯ. В последнее время при исследовании патогенеза злокачественных новообразований яичников большой интерес ученых во всем мире вызывает изучение роли генов иммунного ответа и воспаления. В статье представлены результаты исследования роли аллельных вариантов генов NFKB1 (rs28362491), IL6 (rs1800795), IL18 (rs1946518) и IL23R (rs7517847, rs10889677) в патогенезе РЯ у женщин из Республики Башкортостан. Материалом для работы послужили образцы ДНК женщин с установленным диагнозом «рак яичников» (n=238) и здоровых индивидов (n=284). Генотипирование образцов ДНК проводили методами полимеразной цепной реакции (ПЦР) с последующим анализом полиморфизма длин рестрикционных фрагментов и аллель-специфичной ПЦР. Установлено, что генетическими маркерами риска развития рака яичников для женщин русской этнической принадлежности пременопаузального возраста являются генотипы rs28362491*ID в гене NFKB1 и rs1946518*СA в гене IL18. Носительство генотипов rs1800795*GG в гене IL6 и rs10889677*CС в гене IL23R для женщин татарской этнической принадлежности в постменопаузе является протективным фактором. Для татар с генотипом rs10889677*CА в гене IL23R в постменопаузе, напротив, было показано повышение риска развития заболевания. К маркерам пониженного риска развития РЯ у русских также можно отнести генотип rs1946518 *AA в гене IL18, который был отмечен как протективный фактор для женщин как в пре-, так и постменопаузе, а также у больных данной онкопатологией с начальными и запущенными стадиями заболевания. При сравнительном анализе распределения частот аллелей и генотипов полиморфного варианта rs7517847 в гене IL23R среди больных РЯ и здоровых доноров статистически значимых различий между исследуемыми группами не обнаружено. Ovarian cancer (OC) is one of the most common malignancyof the female reproductive system. High rates of morbidity and mortality from this type of cancer indicate the need for a deeper understanding of the molecular genetic basis of the disease, which in turn will contribute to the development of new approaches to the diagnosis and treatment of OC. Recently, when studying the pathogenesis of malignant neoplasms of the ovaries, a great interest of scientists around the world is directed to studying the role of the immune response and inflammation genes in the development of the OC. At this work presents the results of the study of the role of the polymorphic loci of the genes NFKB1 (rs28362491), IL6 (rs1800795), IL18 (rs1946518) and IL23R (rs7517847, rs10889677) in the pathogenesis of ovarian cancer in women from the Republic of Bashkortostan.The material for the work was the DNA samples of women with an established diagnosis of ovarian cancer (n = 238) and healthy individuals (n = 284). Genotyping of DNA samples was performed using polymerase chain reaction (PCR), followed by analysis of restriction fragment length polymorphism and allele-specific PCR. It has been established that the genetic markers of the risk of developing ovarian cancer for women of Russian ethnicity at premenopausal age are the genotypes rs28362491* ID in the NFKB1 gene and rs1946518 * CA in the IL18 gene. The carrier of the rs1800795 * GG genotypes in the IL6 gene and rs10889677 * CС in the IL23R gene for post-menopausal women of Tatar ethnicity is a protective factor. For Tatars with the rs10889677 * CA genotype in the IL23R postmenopausal gene, on the contrary, an increased risk of developing the disease was shown. Markers of a reduced risk of developing ovarian cancer in Russians can also include the rs1946518 * AA genotype in the IL18 gene, which was noted as a protective factor for women in both pre- and postmenopausal women, as well as in patients with this oncopathology with initial and advanced stages of the disease. A comparative analysis of the frequency distribution of alleles and genotypes of the polymorphic variant rs7517847 in the IL23R gene among patients with OC and healthy donors did not reveal statistically significant differences between the studied groups.

IL-18 Gene Polymorphisms Impacts on Its Serum Levels in Prostate Cancer Iraqi Patients

Prostate cancer is one of the most common types of cancer in men. A total of 110 Iraqi Arab individuals were included in this study; 60 individuals of them had prostate cancer with increased levels of TPSA (patients group); their age range 52-90 years. They were referred for diagnosis and treatment to the National Al-Amal Hospital for oncology in Baghdad during the period from July 2017 to October 2017. While the other 50 apparently healthy subjects were the control group, their age range similar to patients group. Sera and blood samples were collected from all patients and controls than used to assess for the level of IL-18 and DNA extraction, respectively. The polymorphisms were analyzed using polymerase chain reaction-single specific primer (PCR-SSP), at the position -137 G\C (rs187238) in the promoter of IL18 gene. The genetic polymorphism of the IL18 gene promoter -137G/C (rs187238) was determined and presented with three genotypes (GG, GC, and CC) in prostate cancer patients and controls. Testing for Hardy-Weinberg (H-W) equilibrium revealed that Prostate cancer patients showed insignificant variation in the distribution of IL-18 -137 genotypes (P> 0.05). While the control samples showed significant variation (p ≤0.05) between the observed and expected. Comparing patients with controls indicated that IL-18-137 alleles or genotypes showed no association with the risk of prostate cancer development in Iraqi Arab population or protection against them. Serum level of IL-18 was highly significant (P ≤ 0.001) increased in patients compared to control. The IL-18 serum levels differences in GG and GC genotypes was significant (p <0.05) between patients and control. While there were no significant differences between the three IL-18 -137 genotypes inpatient or in controls.

IL18 Gene Polymorphism Influences Age of Onset of DM1 in African Ancestry Brazilians

The aim of this study was to investigate the relationship of two single nucleotide polymorphisms (SNPs) in the interleukin-18 (IL18) gene (rs187238, g.-137G > C; rs1946518, g.-607C > A) and one SNP of the IL12B gene (rs3212227 g.*159A > C, 3′UTR) with the age of onset for type 1 diabetes mellitus (DM1). A total of 1,101 patients with DM1 enrolled in 13 centers from different regions of Brazil were genotyped with TaqMan assay and classified according to the ancestry. Our results show that an SNP in IL18 gene could be associated with DM1 age onset, taking into account that this studied variation affects gene expression.