Association of a placental Interleukin-6 genetic variant (rs1800796) with DNA methylation, gene expression and risk of acute chorioamnionitis

Abstract

Background Acute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 ( IL6 ) may contribute to the placenta’s inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA. Currently, there is remarkably little research on the role of fetal (placental) genetic variation in aCA. We aimed to explore the associations between genetic variants in candidate immune-system genes and susceptibility towards inflammatory responses in the placenta, which is linked to a strong inflammatory response in the newborn. Methods DNA samples from 269 placentas (72 aCA cases, 197 non-aCA cases) were collected for this study. Samples were genotyped at 55 ancestry informative markers (AIMs) and 16 additional single nucleotide polymorphisms (SNPs) in 12 candidate innate immune system genes using the Sequenom iPLEX Gold Assay. Publicly available datasets were used to obtain DNA methylation (GSE100197, GSE74738, GSE115508, GSE44667, GSE98224) and gene expression data (GSE44711, GSE98224). Results Differences in IL6 placental allele frequencies were associated with aCA (rs1800796, p = 0.04) with the CC genotype specifically implicated (OR = 3.1; p = 0.02). In a subset of the placental samples ( n = 67; chorionic villi), we showed that the IL6 SNP (rs1800796) was associated with differential DNA methylation in five IL6 -related CpG sites (cg01770232, cg02335517, cg07998387, cg13104385, and cg0526589), where individuals with a CC genotype showed higher DNA methylation levels than individuals carrying the GG genotype. Using two publicly available datasets, we observed that the DNA methylation levels at cg01770232 negatively correlated with IL6 gene expression in the placenta ( r = − 0.67, p < 0.004; r = − 0.56, p < 2.937e-05). Conclusions We demonstrated that the minor C allele at the IL6 SNP (rs1800796), which is largely limited to East Asian populations, is associated with the presence of aCA. This SNP was associated with increased DNA methylation at a nearby MEPC2 binding site, which was also associated with decreased expression of IL6 in the placenta. Decreased expression of IL6 may increase vulnerability to microbial infection. Additional studies are required to confirm this association in Asian populations with larger sample sizes. ...

Sex Differences Are Here to Stay: Relevance to Prenatal Care

“…When considering genomic screening methods, one must consider the frequency at which "risk" variants exist in certain populations. For example, it has been reported that an IL6 variant associated with acute chorioamnionitis risk is only present in East Asian populations [198], and that selection in the progesterone receptor gene may have led to specific polymorphisms that underlie differential rates of progesterone-associated pregnancy complications by population [199]. Other maternal factors associated with risk of adverse pregnancy outcomes include socioeconomic status, comorbid health conditions, and smoking status.…”

Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age

“…Standardized tools were used for assessing child behavior and adjusting our analyses for the major confounding factors in the association between DNA methylation and child behavior. Whether adjusting EWAS for cell heterogeneity is relevant is still debated [74,75]. Epigenetic marks are highly specific to cell types in the placenta as in other tissues.…”

Association study of genetic variations of inflammatory biomarkers with susceptibility and severity of obstructive sleep apnea

“…IL‐6 was the most focused inflammatory biomarker for OSA (Chu & Li, ; Kaditis et al, ; Kurt, Tosun, & Talay, ; Lopez‐Pascual et al, ; Popko et al, ; Shalitin, Deutsch, & Tauman, ; Wu et al, ; Zhong, Xiong, Shi, & Xu, ). IL‐6 rs1800796, a function variant located in the promoter region of IL‐6 , has been evaluated for its association with many kinds of diseases, including cancers, celiac disease, chronic HBV infection, acute coronary syndrome, ischemic stroke, periodontitis, IgA nephropathy, hip fracture, osteoarthritis, acute chorioamnionitis, etc., (Akinyemi et al, ; Amr, El‐Awady, & Raslan, ; Barartabar et al, ; Du, Gao, Zhang, & Wang, ; Eftekhari et al, ; Fernandes et al, ; Fragoso et al, ; Kaditis et al, ; Konwar, Del Gobbo, Terry, & Robinson, ; Li et al, ; Ponce de Leon‐Suarez et al, ; Tang et al, ; Wang, Chen, Zhao, Zhang, & Yu, ; Wang et al, ; Zhang et al, ; Zhang, Mao, & Sun, ; Zhao, Li, & Li, ). Although two previous studies evaluated the associations of IL‐6 rs1800796 with the development of OSA, the results were not significant, which may be caused by the relatively small sample size (Kaditis et al, ; Zhang et al, ).…”