Intronic Polymorphism Associated with Risk of Neurological Disorders in SLE

The transient receptor potential (TRP) ion channel family regulates cross talk between endothelial cells and inflammatory leukocytes. This family of receptors is formed by cation permeable membrane proteins that have a high affinity for Ca++ ions. They may also play an important role in systemic lupus erythematosus (SLE), because overactive Ca++ currents have been described in T and B lymphocytes from SLE patients following membrane receptor activation.

Recent research indicates cells from patients with neuropsychiatric manifestations of SLE who have the transient receptor potential canonical channel 6 (TRPC6) rs7925662 intronic single nucleotide polymorphism (SNP) may be more dependent on TRPC6 for the generation of calcium currents than are individuals without this SNP. These patients are said to have the TT genotype. Giuseppe A. Ramirez, a graduate student at the IRCCS San Raffaele Hospital & Scientific Institute, Italy, and colleagues published their findings in the December 2018 issue of the Journal of Neuroimmunology.¹

The researchers began their investigation with 151 SLE patients with who had a median disease duration of 12 years at the time of assessment. Of these, 43.1% had a history of lupus nephritis and 21.9% had a history of neuropsychiatric SLE.

Researchers found the TT genotype associates with a higher incidence of neuropsychiatric SLE. In contrast, no significant difference exists in the cumulative neuropsychiatric SLE incidence between two other TRPC6 genotypes (CC and TC). Moreover, the TT genotype did not associate with lupus nephritis nor did it associate with other non-renal, non-psychiatric SLE phenotypes.

The team next investigated the role of TRPC6 in Ca++ mobilization. They characterized the effects of TRPC6 on the function of peripheral blood mononuclear cells from 18 patients with SLE and eight healthy controls with a known genotype. Although Ca++ influx did not differ between the cells of healthy controls and patients with SLE, researchers found enhanced TRPC6 calcium influx in peripheral blood mononuclear cells of neuropsychiatric SLE patients. These same cells also had a higher sensitivity to activation induced cell death, an important factor in immune cell homeostasis.

“We observed that the TT genotype influences functions known to be regulated by Ca++-dependent pathways in immune cells, such as the secretion of cytokines and [activation induced cell death],” write the authors in their discussion. “TRCP6 opening, however, does not influence all events regulated by Ca++, suggesting a selective action. The secretion of IL-17 in particular, which is relevant for SLE pathogenesis and dependent on variations in the intracellular Ca++ concentration, is dependent on TRCP6 opening in stimulated cells of SLE patients.”

The researchers also found a decreased concentration of IL-4 in the supernatant of activated T cells from SLE patients who carry the TT genotype. “Our findings suggest that the TRPC6 genotypes influence the function of circulating immune cells and associate with the risk of developing [neuropsychiatric SLE],” write the authors.

TRPC6 appears to influence calcium currents, apoptosis rates and cytokine secretion, all in a disease- and genotype-dependent manner. Thus, gene variants associated with the intron polymorphism may at least partially account for the heterogeneity of SLE patients.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Ramirez GA, Coletto LA, Bozzolo EP, et al. The TRPC6 intronic polymorphism, associated with the risk of neurological disorders in systemic lupus erythematous, influences immune cell function. J Neuroimmunol. 2018 Dec 15;325:43–53.