Cell lineage-specific methylome and genome alterations in gout

Abstract

In this study, we examined data from 69 gout patients and 1,455 non-gout controls using a MethylationEPIC BeadChip assay and Illumina HiSeq platform to identify lineage-specific epigenetic alterations and associated genetic factors that contributed to gouty inflammation. Cell lineage-specific differentially methylated sites were identified using CellDMC after adjusting for sex, age, alcohol drinking, smoking status, and smoking history (total pack-years). Different cell lineages displayed distinct differential methylation. Ingenuity Pathway Analysis and NetworkAnalyst indicated that many differential methylated sites were associated with interleukin-1β expression in monocytes. On the UCSC Genome Browser and WashU Epigenome Browser, metabolic trait, cis-methylation quantitative trait loci, genetic, and functional annotation analyses identified nine methylation loci located in interleukin-1β-regulating genes ( PRKCZ, CIDEC, VDAC1, CPT1A, BIRC2, BRCA1, STK11, and NLRP12 ) that were associated specifically with gouty inflammation. All nine sites mapped to active regulatory elements in monocytes. MoLoTool and ReMap analyses indicated that the nine methylation loci overlapped with binding sites of several transcription factors that regulated interleukin-1β production and gouty inflammation. Decreases in PRKCZ and STK11 methylation were also associated with higher numbers of first-degree relatives who also had gout. The gouty-inflammation specific methylome and genome alterations could potentially aid in the identification of novel therapeutic targets.

Where Epigenetics Meets Food Intake: Their Interaction in the Development/Severity of Gout and Therapeutic Perspectives

“…Additionally, the role of DNA methylation in gout was demonstrated through the discovery of a variant (rs2228611) in the DNA MethylTransferase 1 (DNMT1) gene whose presence is statistically increased in gout patients compared to controls (9). In line with this information, an innovative multi-OMICs study, in which the cell-specific methylome was compared between gout patients and controls, revealed that many differentially methylated gene regulatory genomic sites were associated with IL-1b expression in monocytes (55).…”

“…Because epigenetics has now been identified as an important player in gouty arthritis, we thought to re-evaluate the impact of diet in light of nutrient-derived epigenetic modifiers. As described in the previous section, a significant number of epigenetic factors potentially affect gout onset and can contribute to further inflammation events worsening the symptoms (9,55). Among such factors influencing epigenetic changes are multiple compounds (listed in Table 1) that are commonly found in one's diet.…”

Sex Differences on the Pharmacokinetics of Drugs for Children with Chronic Kidney Disease: A Narrative Review

“…Many genes possess hormone response elements in the region of their target genes, which can interfere with the transcription of target genes. The expression of DNA methylation is also under sex hormones (estrogens and androgens) control [21]. Hormonal and genetic factors have also been shown to play a relevant role in explaining these differences in CKD, as demonstrated by several experimental studies, showing an overall protective role for estrogens and progesterone [22][23][24].…”

“…Studies have shown that collagen-vascular diseases and autoimmune disorders affect females three to ten times more than males [27]. Environmental stressors-induced epigenetic alteration such as chemical exposures, drugs, and infections during pregnancy, ureter-placental hypoxia, and maternal undernutrition may lead to prematurity and LBW infants and the risk of long-term hypertension and metabolic syndrome leading to the development of CKD, in children and adults [14,15,20,21].…”

Association between night shift work and methylation of a subset of immune-related genes

“…BIRC2 (Baculoviral IAP Repeat Containing 2) encodes a member of the inhibitors of apoptosis (IAP) family of proteins. BIRC2 expression is downregulated by promoter hypermethylation ( 49 , 50 ), which was also associated with increased IL-1β production ( 49 , 51 ). Similarly, hypermethylation of the SIRT1 gene (encoding the Sirtuin 1, a deacetylase whose downregulation has been found in many disease conditions) correlates with lower transcript levels and with an increased risk of inflammatory and metabolic diseases ( 52 , 53 ).…”