Gene Variant May Increase Lymphoma Susceptibility in Young-onset Sjögren’s

A variant of the LILRA3 gene may be associated with greater lymphoma susceptibility in a group of Sjögren’s syndrome patients with disease onset prior to age 40, a study reports.

The variant could be a potential biomarker of lymphoma risk in those patients, but researchers caution that more studies are needed in larger populations to confirm these findings.

The study, “Leukocyte Immunoglobulin-Like Receptor A3 (LILRA3): A Novel Marker for Lymphoma Development among Patients with Young Onset Sjogren’s Syndrome,” was published in the Journal of Clinical Medicine.

Sjögren’s syndrome is a chronic autoimmune disease primarily affecting women older than 40. Due to several genetic, physiological, and clinical risk factors, a small subpopulation of those with the disease develops non-Hodgkin’s lymphoma (NHL).

Mutations in the immune-modulating gene LILRA3 have been described as a risk factor for both Sjögren’s and NHL. This led researchers in Greece to examine whether these mutations are among the genetic factors linked to increased lymphoma risk in Sjögren’s patients.

The team investigated two variants of the LILRA3 — a normal, functioning one that results in normal protein levels, and another variant in which a portion of the gene is deleted, causing LILRA3 protein deficiency. 

The analysis included 783 participants, of whom 101 were Sjögren’s patients with a current or previous lymphoma diagnosis; 301 were Sjögren’s patients without a personal history of lymphoma, and 381 were age-, race-, and sex-matched healthy controls.

The patients were grouped by age at disease onset as younger-onset (younger than 40) and older onset (40 and older). Depending on the number of risk factors for lymphoma, non-lymphoma patients also were grouped as high/medium risk (more than two risk factors) and low-risk (one to two risk factors).

While controls and Sjögren’s patients with or without lymphoma had a similar frequency of the functional LILRA3 variant, this variant was significantly more common among lymphoma patients with young-onset Sjögren’s compared with controls (100% vs. 82.9%).

This increased prevalence was not observed in people with lymphoma and older-onset Sjögren’s, or in either age group of non-lymphoma patients. 

Yet, among non-lymphoma patients, the variant was significantly more common in those with a high/medium risk of lymphoma than in low-risk patients (91.8% vs. 78.3%).

Consistent with how much protein each variant originates, an analysis to LILRA3 protein blood levels found significantly higher levels in lymphoma patients (1.27 nanograms/mL, ng/mL) than in controls (0.38 ng/mL), but not in non-lymphoma patients (0.63 ng/mL).

Among young-onset patients, the levels of this protein were significantly higher in the two Sjögren’s groups than in controls, and also were elevated in lymphoma patients compared with non-lymphoma Sjögren’s patients. 

In older-onset patients, no significant differences were observed in LILRA3 protein levels compared to controls, or between lymphoma and non-lymphoma patients.

“These findings support a potential role of the LILRA3 molecule in the pathogenesis of [Sjögren’s syndrome]-related lymphoma, giving an insight into the aggressive nature of young onset [Sjögren’s syndrome],” the research team wrote, noting that the study was limited by the small sample size, due to the rarity of the disease.

“Further studies in larger populations are needed to confirm these findings and clarify the contribution of LILRA3 in promoting chronic inflammatory pathways,” they added.