Defining Mechanistic Links Between the Non-Coding Variant rs17673553 in CLEC16A and Lupus Susceptibility

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Systemic lupus erythematosus (SLE) is an autoimmune disease with complex genetic underpinnings.
• Genome-wide association studies (GWAS) identified a susceptibility locus at 16p13 for SLE, but the causal variant and its mechanism remain elusive.

Purpose of the Study:

• To identify the functional variant at 16p13 associated with SLE.
• To elucidate the molecular mechanism by which this variant contributes to SLE pathogenesis, focusing on autophagy regulation.

Main Methods:

• Bioinformatic analysis to prioritize functional variants.
• CRISPR-based genome editing in B cells.
• Luciferase reporter assays and ChIP-qPCR to assess enhancer activity.
• Assessment of autophagy levels in wild-type and knock-out cells.

Main Results:

• The intronic variant rs17673553 was identified as a potential causal variant affecting enhancer function.
• The risk allele of rs17673553 enhances binding of histone marks (H3K27ac, H3K4me1), CTCF, and transcription factors GATA3 and STAT3.
• This leads to altered expression of target genes, including CLEC16A, and impacts autophagy levels.
• CRISPR editing confirmed the regulatory role of rs17673553 on CLEC16A and autophagy.

Conclusions:

• The rs17673553 locus, particularly the risk allele, drives allele-specific chromatin modifications and transcription factor binding.
• This mechanism mechanistically regulates autophagy-associated genes like CLEC16A, potentially explaining its association with SLE.
• The findings provide a molecular basis for the 16p13 SLE susceptibility signal.