The sodium‐dependent glucose cotransporter SLC5A11 as an autoimmune modifier gene in SLE

Abstract

Genetic studies in several human autoimmune diseases suggest that the pericentromeric region of chromosome 16 might harbor an autoimmune modifier gene. We hypothesized that the sodium-dependent glucose cotransporter gene SLC5A11 is such a gene, and so might interact with immune-related genes. Herein, this hypothesis was tested in a genetic evaluation of the multiple gene effect in systemic lupus erythematosus (SLE). We used the case-control candidate gene association approach. Eight immune-related genes involved in inflammation and autoantibody generation and clear-up [interleukin 1 receptor antagonist (IL1RN), interleukin 1-beta (IL1-beta), tumor necrosis factor-alpha (TNF-alpha), lymphotoxin-alpha (LTA), tumor necrosis factor ligand superfamily, member 6 (TNFSF6), programmed cell death 1 (PDCD1), C2, and complement component 4 (C4)] were selected for study. Frequency of each candidate's genotype and allele between case and control were compared. Results were stratified by reanalyzing genotype data with relevant symptoms. Finally, improved computational data mining was used to analyze the phenotypes in a large data set. In the frequency analysis, only IL1-beta was significantly associated with SLE. Stratification analysis showed a significant association with SLE symptoms between SLC5A11 and the other immune-related genes, with the exceptions of TNFSF6 and C4. SLC5A11 was significantly associated with low C4 (as was TNF-alpha), anti-Smith antibody (anti-Sm) (as was C2), serositis, and alopecia. Finally, SLC5A11 interacted with PDCD1, TNF-alpha, LTA, and C4. After our study, we concluded that SLC5A11 is involved with some immune effects and interacts with immune-related gene(s), consistent with its function as an autoimmune modifier gene. Furthermore, SLC5A11 might induce apoptosis through the TNF-alpha, PDCD1 pathway. The present genotype-phenotype mapping approach should be applicable to genetic study of other complex diseases.

Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

“…28 A candidate gene association analysis performed in 95 Korean patients with SLE implicated SLC5A11 polymorphisms in susceptibility to SLE and select disease manifestations. 29 These authors identified gene-gene interactions between SLC5A11 and immune-function genes (TNF, LTA, and C4) and the T and B cell costimulatory receptor gene (PDCD1), a confirmed LN susceptibility locus among European descendants. 30 Hyaluronan synthase 2 (HAS2) located on 8q24 leads to the production of the extracellular matrix component hyaluronan.…”

Update on Lupus Nephritis

“…Variants in SLC5A11 may mediate a decrease in serum and an increase in urine myo-inositol, suggesting an active role of SLC5A11 in proximal tubule inositol reabsorption (38). Additionally, or through inositol regulation, SLC5A11 may mediate apoptosis through the programmed cell death and TNF-a pathways (39).…”

Meta-analysis of TNF-α promoter –308A/G polymorphism and SLE susceptibility in Asian populations

“…Characteristics of eligible studies (Table 1) Characteristics of studies included in the current meta-analysis are presented in Table 1 [11][12][13][14][15][16][17][18][19][20][21][22]. There were 111 papers relevant to the searching words in PubMed ( Fig.…”

“…Of these, 31 did not explore the association between TNF-gene polymorphism and SLE susceptibility and were excluded. Remaining 28 studies were retrieved for more detailed evaluation [11][12][13][14]. Of these, 18 were not conducted in Asian populations and were excluded [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”