Gene polymorphisms of IL-1β (C511T), IL-17A (G197A), IL-12B (A1188C), TNFα (G308A) and IL-4 (C589T) associated with threat of early reproductive losses
Prevalence of threatened miscarriage is 16-25% of all pregnancies. The symptomatics of the threatened miscarriage in the first trimester may develop due to conversion of initial inflammatory reaction that disturbs the intersystemic and local interactions in the endometrium, followed by placental insufficiency, intrauterine fetal affection and spontaneous abortion. The aim of our work was to study the association between single nucleotide polymorphisms (SNPs) of some cytokine genes, e.g., IL-1β (C511T, rs16944), IL-17A (G197A, rs2275913), IL-12B (A1188C, rs3212227), TNFα (G308A, rs1800629), and IL-4 (C589T, rs2243250) and the risk of early reproductive losses among residents of Adyghe Republic (RA). The work was carried out at the Immunogenetic Laboratory of our Research Institute of Complex Problems. The allelic variants of cytokine genes were detected by SNP-method in 106 samples of genomic DNA in women with the threatened abortion in 1st trimester (n = 58) and the uncomplicated gestation (n = 48). SNP-typing of polymorphic variants of cytokine genes IL-1β, IL-17A, IL-12B, TNFα and IL-4 was carried out by PCR (polymerase chain reaction) with allele-specific primers and electrophoretic detection of results on test systems of (Litech, Moscow). Statistical analysis of experimental data was carried out by SPSS Statistical program 17.0. The correspondence of SNP distributions to expected values at Hardy—Weinberg equilibrium and comparison of allelic variants/ genotypes frequencies were performed using the χ2 criterion (Chi-square with Yates correction), odd ratios (OR) detected at significance level p < 0.05 and 95% confidence interval (95% CI). Reliability of the differences for the SNP frequencies for small samples was evaluated using the Fisher’s exact criterion. Heterozygous variant (C511T; OR = 3.46; 95% Cl: 1.04-11.54) and homozygous “mutant” genotypes (T511T; OR = 5.71; 95% Cl: 1.12-29.09) of the main proinflammatory IL-1β was significantly associated (p < 0.05) with the risk of developing threatening miscarriage in the Adygea residents. The -511Т allele of IL-1β gene, and -1188C variant of IL-12B gene increase the risk of the early termination of pregnancy, respectively, 5.8-fold (95% Cl: 2.4213.92; p = 0.00004), and 2.97-fold (95% Cl: 1.23-7.19; p = 0.01). The “mutant” -511T allelic variant of the IL-1 p gene is associated with the risk of developing a symptome complex of threatening miscarriage in Russian ethnic group (p = 0.0001; OR = 14.09), and in Adygea ethnic group (p = 0.02; OR = 8.17), which is almost undetectable in women with normal pregnancy in the first trimester. Thus, only С511Т (rs16944) in IL-1β gene and A1188C (rs3212227) in IL-12B gene of the five typed cytokine genes may be used as marker polymorphisms of gestational distress for the women in Adygea
