Objective Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker. Methods IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren’s syndrome (pSS) were used for validation. Results Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage. Conclusions The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE.

Twenty-nine individuals (41.43%) presented an affected unilateral posterior canal. Fifteen patients (21.43%) presented a pure horizontal direction-changing positional nystagmus consistent with a diagnosis of horizontal canal BPPV. Twelve individuals (17.14%) presented a unilateral down-beating nystagmus, suggesting possible anterior canal BPPV. In addition, 14 patients (20%) showed multiple positional nystagmus during the examination corresponding to simultaneous multi-canal BPPV, 5 had bilateral posterior canal BPPV and 2 presented a positional down-beating nystagmus in both left and right Dix-Hallpike manoeuvres and the head-hanging manoeuvre, which is highly suggestive of anterior canal BPPV. However, seven individuals showed positional horizontal and vertical side-changing nystagmus that could not be explained by single-canal BPPV. These patients with multiple positional nystagmus showed changing patterns of positional nystagmus at follow-up.

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These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.

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