IL13RA1 – Systemic Sclerosis

The association between IL13RA1 (HGNC:5974) and systemic sclerosis (MONDO_0005100) has been evaluated in multi‐patient genetic studies with conflicting outcomes. A large European multicohort study involving 2488 patients with systemic sclerosis and 2246 controls found no significant association between polymorphisms in interleukin receptor genes, including IL13RA1, and disease susceptibility or gene expression levels (PMID:22045834).

In contrast, a separate study assessing polymorphisms in both IL13RA1 and IL13RA2 reported associations only in IL13RA2, with IL13RA1 not showing robust evidence for disease involvement (PMID:16981293). This discrepancy raises questions about the potential contribution of IL13RA1 to systemic sclerosis, particularly in light of the observed associations being confined to its paralog.

Genetic evidence for IL13RA1 remains limited as no clear pathogenic variants, formatted as a complete HGVS string (e.g. a variant starting with “c.” and including a protein annotation), have been conclusively reported. Although the 2012 study genotyped a SNP in IL13RA1 (43163G>A/rs6646259), the data were not presented in the mandated HGVS format, and no further genotype–phenotype correlation has been established.

No dedicated functional or experimental studies have been reported that assess the mechanistic role of IL13RA1 in systemic sclerosis. While several in vitro and transcript expression analyses were undertaken in peripheral blood leukocytes, these did not provide functional correlates to support a pathogenic mechanism for IL13RA1, such as haploinsufficiency or dominant-negative effects.

Overall, the cumulative evidence for an association between IL13RA1 and systemic sclerosis is disputed. The robust negative finding from the larger study and the lack of supportive functional data suggest that IL13RA1 should not currently be considered a diagnostic marker for systemic sclerosis. This differentiation is critical for clinical decision‑making, commercial applications, and guiding future research.

Key Take‑home: Current data do not support a clinically actionable association between IL13RA1 and systemic sclerosis, underscoring the need for further investigation into alternative molecular contributors to the disease.

References

• The Journal of Rheumatology • 2012 • Polymorphisms in the interleukin 4, interleukin 13, and corresponding receptor genes are not associated with systemic sclerosis and do not influence gene expression PMID:22045834
• The Journal of Rheumatology • 2006 • IL13RA2 gene polymorphisms are associated with systemic sclerosis PMID:16981293

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