Interleukin 10 Gene Promoter Polymorphisms in Women with Pregnancy Loss: Preferential Association with Embryonic Wastage1

Abstract

Interleukin 10 (IL10) is associated with maternal immunotolerance. IL10 also down-regulates decidual cell tissue factor expression, the main molecule triggering coagulation activation: this antithrombotic effect may protect the umbilicoplacental vasculature from the 10th wk of gestation onward. IL10 down-regulation may thus dispose to early pregnancy loss (PL) due to maternal immunotolerance defect or late pregnancy failure due to placental vascular insufficiency. IL10 gene promoter polymorphisms associated with cytokine down-regulation may help to identify the actual and probable mechanisms of IL10 modulation in pregnancy outcomes. We investigated the following four IL10 promoter polymorphisms associated with IL10 down-regulation: two single-nucleotide polymorphisms rs1800871 and rs1800872 and two polymorphic CA repeat microsatellites IL10 X78437.2:g8134CA(14_29) and IL10 X78437.2:g.5325CA(11_15). Each microsatellite was analyzed as a biallelic polymorphism. Based on a review of the literature, we define a short allele and a long allele for each microsatellite. We compared their frequencies in early PL occurring before 10 wk of amenorrhea (n = 342) and in PL occurring later on (n = 123). The mutated alleles rs1800871T (odds ratio, 3.083; 95% confidence interval, 1.984-4.792) and rs1800872A (odds ratio, 3.013; 95% confidence interval, 1.924-4.719) were associated with early PL. The haplotype rs1800872A/rs1800871T/X78437.2:g.8134CA[14_25]/X78437.2:g.5325CA[11_13], which includes the two mutated alleles, was significantly associated with the risk of early PL in a dose-dependent manner. Positivity for one haplotype was significantly associated with a 5.6-fold increase in the risk of early pregnancy failure, and positivity for two haplotypes was associated with an 8-fold increase in risk. In women with PL, some polymorphisms of the IL10 gene promoter seem to be constitutional risk factors for early (embryonic) pregnancy failure.

Maternal Interleukin Genotypes Are Associated With NICU Outcomes Among Low-Birth-Weight Infants

“…We were able to eliminate genotyping error; therefore, we believe HWE violation was due to a biased sample of women who delivered preterm infants, which enriched for the alleles under investigation. The SNPs included in this study have been implicated in a variety of obstetrical complications including SGA (rs2070874 and rs2243250; Engel et al, 2005), spontaneous preterm birth (rs1800795; Wu et al, 2013), and pregnancy loss (rs1800871 and rs1800872; Cochery-Nouvellon et al, 2009). …”

“…IL-10 is a regulatory cytokine, and SNPs in the promoter region of the IL10 gene are associated with IL-10 levels (Capasso et al, 2007; Lowe, Galley, Abdel-Fattah, & Webster, 2003; Qaddourah et al, 2014; Yilmaz, Yentur, & Saruhan-Direskeneli, 2005). Maternal IL10 genetic variation has been associated with pregnancy loss (Cochery-Nouvellon et al, 2009; Qaddourah et al, 2014), perhaps due to the role of IL-10 in maintaining maternal–fetal tolerance (Denney et al, 2011). …”

Association of interleukin-10 gene promoter polymorphisms with recurrent pregnancy loss: a meta-analysis

“…1, 49 articles were excluded, of which 32 were duplicate ones and 17 with no relation to this topic. The remaining 17 studies were full-text reviewed, and five studies were excluded, among which, one was not about recurrent abortion and not a case-control study [13], two were of unavailable genotype [32,33] and the other two were metaanalysis [25,26]. Finally, in the current study, 12 eligible case-control studies that meet the inclusion criteria were included in our meta-analysis [14,16,17,[19][20][21][22][23][24][34][35][36].…”

“…Several studies have identified single-nucleotide polymorphisms (SNPs) of IL-10 gene can significantly influence the levels of IL-10 production and key obstetric complications, particularly the promoter variants control IL-10 secretion [13][14][15]. Though a number of studies have been conducted to investigate the association between promoter polymorphisms of IL-10 with RPL, the results are not consistent [14][15][16][17][18][19][20][21][22][23][24].…”

Cytokine gene polymorphisms and early pregnancy loss

“…Известно, что IL-10 принимает активное учас-тие в обеспечении иммунотолерантности материнского организма к развивающемуся зародышу. Кроме того, IL-10 обеспечивает снижение уровня экспрессии деци-дуальными клетками ряда молекул -активаторов коа-гуляции (Cochery-Nouvellon et al, 2009). Наличие в ге-нотипе аллелей -31 Т гена IL-1β или -592 А гена IL-10 предполагает повышение уровня провоспалительных цитокинов в тканях-мишенях.…”