DNA methylation alterations in systemic lupus erythematosus: A systematic review of case-control studies

Abstract

Background Traditionally, the diagnosis and monitoring of disease activity in systemic lupus erythematosus (SLE) are contingent upon clinical manifestations and serological markers. However, researchers are struggling to find biomarkers with higher sensitivity and specificity. DNA methylation has been the most studied epigenetic feature in SLE. So, in this study, we performed a systematic review of studies about DNA methylation alterations in SLE patients compared to healthy controls. Methods By searching PubMed, Scopus, and Google Scholar up to July 2022, all case-control studies in which DNA methylation of specific genes was assessed by a non-high-throughput technique and passed the quality of bias assessment were included. Results In total, 44 eligible studies underwent a data extraction process. In all, 3471 SLE patients and 1028 healthy individuals were included. Among the studies that reported the patients’ gender ( n = 2853), 89.41% were female and 10.59% were male. Forty studies have been conducted on adult patients. The number of works on fractionated and unfractionated blood cells was almost equal. In this regard, 22 studies were conducted on whole blood or peripheral blood mononuclear cells and two studies on unfractionated white blood cells. Sorted blood cells were biological sources in 20 studies. The most investigated gene was IFI44L. Sensitivity, specificity, and diagnostic power of methylation levels were only reported for IFI44L in five studies. The most employed methylation profiling method was bisulfite sequencing polymerase chain reaction. The correlation between methylation patterns and clinical parameters was explored in 22 studies, which of them 16 publications displayed a remarkable association between DNA methylation status and clinical indices. Conclusions The methylation status of some genes especially IFI44L, FOXP3, and MX1 has been suggested as promising SLE biomarkers. However, given the conflicting findings between studies because of potential confounders such as different sample types, methylation profiling methods, and ethnicity as well as shared DNA methylation patterns of SLE and other autoimmune diseases, DNA methylation biomarkers are currently not reliable diagnostic biomarkers and do not represent surrogate markers of SLE disease activity. Future investigations on a larger scale with the discarding of limitations of previous studies would probably lead to a consensus.

Significant heightened methylation levels of RUNX3 gene promoter in patients with systemic lupus erythematosus

“…This is consistent with the findings of three previous studies on methylation analysis in SLE patients, specifically a potential biomarker called IFI44 L. 19,23,31 Also, in a recent study, our research team unveiled that the methylation level of the MMP9 gene can appreciably discriminate SLE patients from healthy control population. 18 Furthermore, we observed that SLE patients with renal involvement exhibited higher methylation levels in the RUNX3 promoter sequence compared to those without renal involvement. Additionally, there was a positive correlation between the methylation level of RUNX3 and creatinine concentration, suggesting that abnormal methylation leading to functional disruption of this gene could potentially contribute to lupus nephritis.…”

“…The sample size was calculated regarding the previously reported frequency of GATA3 methylation in the normal general population [15][16][17] and methylation studies in the Iranian SLE patients. [18][19][20][21][22][23] The samples were taken from a vein and stored in tubes containing an anticoagulant called EDTA. The stored samples were kept at a temperature of À20°C for further processing.…”

“…These investigations have revealed various hypo-or hypermethylation patterns. 10 At present, the diagnosis of SLE and assessment of disease activity primarily rely on clinical characteristics and serological markers, including anti-Smith (anti-Sm) antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, anti-nuclear antibodies (ANAs), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), complement proteins (C3 and C4), and C-reactive protein (CRP). 11 However, it has been observed that these factors, when interpreted together, may have limitations in terms of sensitivity and specificity.…”

Significant hypomethylation of MMP9 gene promoter in patients with systemic lupus erythematosus

“…11 Furthermore, differential DNA methylation between SLE patients and healthy people with a variety of hypo- or hypermethylation patterns has been investigated at the level of single genes which are involved in the function of the immune system such as IFI44L , MX1 , FOXP3 , and so on. 12…”

“…11 Furthermore, differential DNA methylation between SLE patients and healthy people with a variety of hypo-or hypermethylation patterns has been investigated at the level of single genes which are involved in the function of the immune system such as IFI44L, MX1, FOXP3, and so on. 12 Currently, the diagnosis of SLE and measurement of disease activity in patients are mainly contingent upon clinical phenotypes and serological markers comprising anti-Smith (anti-Sm) antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, anti-nuclear antibodies (ANAs), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), complement proteins (C3 and C4), and C-reactive protein (CRP). 13,14 Current guidelines for SLE diagnosis propose that the mentioned serological markers should be interpreted together; notwithstanding, some studies have demonstrated the low sensitivity and specificity of these factors.…”