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Biochemistry (Moscow). Papers in Press. Published on August 5, 2019 as Manuscript BM18-321.

Polymorphism of the IL-1β, TNF, IL-1RA and IL-4 Cytokine Genes Significantly Increases the Risk of Preterm Birth

V. S. Belousova1,a*, O. A. Svitich2, E. V. Timokhina1,b*, A. N. Strizhakov1, and I. M. Bogomazova1

1Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, 119991 Moscow, Russia

2Mechnikov Research Institute of Vaccines and Sera, 105064 Moscow, Russia

*To whom correspondence should be addressed.

Received November 19, 2018; Revised April 11, 2019; Accepted May 21, 2019
Preterm birth is not only medical, but also a social problem. Every year, 15 million premature babies are born worldwide, 100,000 of them - in Russia. The global goal of medicine is prevention of preterm labor and identification of risk factors leading to preterm birth. The objective of our study was to find the association between polymorphic markers in the cytokine IL-1β, TNF-α, IL-1Ra, and IL-4 genes and development of preterm labor. The prospective study was conducted in 108 pregnant women with the risk of preterm birth. The main group consisted of 66 women whose pregnancy ended with preterm delivery despite the ongoing therapy. The comparison group included 42 women with the full-term delivery. The dominant T allele of the cytokine IL-1βgene polymorphism rs1143634 (3953C→T) was 7.6 times more common in women with preterm delivery vs. the comparison group (36.4 and 4.8%, respectively; RR, 1.802; 95% CI, 1.420-2.288; p< 0.05); its homozygous form was detected only in women with preterm delivery at the very early gestation age (less than 26 weeks). The dominant proinflammatory allele 2R of the IL-1 receptor antagonist gene (IL-1Ra) was 1.5 times more common in women with preterm delivery than in the comparison group (63.6 and 42.8%, respectively; RR, 1.400; 95% CI , 1.009-1.943;p< 0.05), which make the 2R allele the risk factor for preterm birth. The 2R/2R and 2R/4R genotypes led to a very early and early preterm delivery, respectively. The combination of three or four proinflammatory genotypes was detected only in women with a very early preterm delivery, which confirms that the combination of several proinflammatory genotypes is an extremely unfavorable factor for the full-term pregnancy. Identification of genetic polymorphisms in the interleukin genes at the periconceptional stage will help to prevent the risk of preterm delivery, which will reduce the incidence of preterm births, as well as perinatal morbidity and mortality.
KEY WORDS: preterm labor, cytokines, IL-1β, IL-1Ra, IL-4, IL-4, TNF-α, interleukins, cytokine gene polymorphism