IFI44L Promotor Methylation as a Specific Diagnostic Marker of SLE

The methylation level of the IFI44L promoter can distinguish patients with systemic lupus erythematosus (SLE) from healthy individuals and those with other autoimmune diseases, making it a highly sensitive and specific diagnostic marker for SLE, according to recent data published in the Annals of Rheumatic Diseases.

Previous studies have identified differential methylated genes in SLE, most of which are hypomethylated in patients. There is also a robust hypomethylation of interferon-regulated genes in SLE that are independent of the cell type examined. Therefore, the investigators of the study sought to determine whether specific DNA methylation changes in the peripheral blood can be useful for the diagnosis of SLE.

“The specificity and sensitivity of IFI44L promoter methylation in discriminating between SLE and HC were superior to those of currently available tests,” the authors wrote. “Moreover, IFI44L promoter methylation levels can discriminate between SLE and other autoimmune diseases such as rheumatoid arthritis [RA] and primary Sjogren Syndrome [SS].”

The researchers examined IFI44L promoter methylation levels in the DNA samples of 377 patients with SLE, 353 patients with RA, and 358 healthy controls. They also used 2 independent sets for validation, which included 1144 patients with SLE, 429 patients with RA, 199 patients with primary SS, and 1350 healthy controls.

They found significant hypomethylation in gene samples from patients with SLE, compared to patients with RA, Sjogren’s syndrome, and healthy controls in 2 cytosine-guanine dinucleotides sites within IFI44L promoter.

In the first validation cohort, researchers compared the methylation of SLE patients against healthy controls, and found that methylation at the first site had a sensitivity level of 93.6% and a specificity level of 96.8% at a cut-off methylation level of 75.5%. The second site had a sensitivity level of 94.1% and a specificity level of 98.2% at a cut-off level of 25.5%.

The authors of the study also found that the methylation levels at the first and second sites were significantly lower among SLE patients with renal damage compared with those without renal damage. Patients with SLE also had significantly increased methylation levels at both sites during remission.

Summary and Clinical Applicability

The authors note that an excellent diagnostic biomarker should be highly sensitive and specific for a disease, be feasible, and be reliably detected.

“DNA methylation detection is performed using stable genomic DNA, as compared with RNA that is much more easily degradable,” the authors explained. “In addition, whole blood is easy to collect and pyrosequencing is reproducible and not operator-dependent.”

The FI44L promoter could potentially be an objective and standardized test for SLE. 

Limitations and Disclosures

The results of the study also showed that DNA methylation levels was lower among SLE patients with renal involvement, which is consistent with previous studies.

“Although our results suggest that the DNA methylation level of IFI44L promoter may be associated with renal damage in patients with SLE, it does not seem to be a good biomarker for renal damage due to a low AUC value between SLE with renal damage and SLE without renal damage,” the authors added.

Reference

Zhao M, Zhou Y, Zhu B, et al. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis. 2016; doi: 10.1136/annrheumdis-2015-208410.