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.
The interleukin-1 receptor antagonist (IL1RN or IL-1Ra) is a natural antagonist of IL-1-beta. Using IL1RN as a possible marker in patients with systemic lupus erythematosus (SLE), we evaluated whether uIL1RN single nucleotide polymorphisms (SNPs) were associated with the pathogenesis of SLE in Taiwanese, and specifically whether IL1RN (rs315952) was significantly associated with end-stage renal disease. We examined IL1RN isoform expression patterns in patients with SLE to determine whether the expressions play a role in the pathogenesis of SLE. Both case-control and family-based association studies were used. For the case-control study, 104 patients with SLE and 97 normal controls were recruited, and for the family-based study, 11 families with SLE without renal disorder were recruited from the 104 patients with SLE. Eight IL1RN SNPs (rs2234678, rs2234679, rs315951, rs315952, rs419598, rs432014, rs447713, and rs451578) were selected for the family-based study. Reverse-transcriptase-polymerase chain reaction (RT-PCR) was used to determine the expression pattern of each isoform. Our results showed that IL1RN (rs315952) was significantly associated with SLE in patients without renal disorder in the family-based study, after disease stratification, but was not significantly associated with SLE in the case-control study. In the family-based study, the haplotype of IL1RN (AGCCTTAG) was significantly associated with SLE (chi2 = 11.714, P < 0.001). Using RT-PCR to determine the expression pattern of the IL1RN isoforms, we found different expression patterns between normal controls and patients with SLE, with an addition of IL1RN isoform4 or the low expression of IL1RN isoform1. We concluded that IL1RN and its isoforms were involved in the pathogenesis of SLE.
Complement component 2 (C2), an early member of the classical pathway, mainly participates in apoptotic cell clearance. We hypothesize that C2 polymorphism may confer genetic susceptibility to complement dysfunction in systemic lupus erythematosus (SLE). The major aim of our study was to investigate the clinical and serological associations of C2 variants in Chinese patients with SLE. The single-nucleotide polymorphism (rs2844455, G/A SNP) located in the intron region of C2 gene was genotyped by direct sequencing in 95 SLE patients and 95 matched normal control subjects. The gene expression profiles were generated by quantitative real-time polymerase chain reaction (PCR) and reverse transcription PCR. Our results showed that the AA genotype was observed more frequently in SLE patients than in normal control subjects (22.1% vs 9.5%, P < 0.05). The A allele was strongly associated with the occurrence of hair loss, photosensitivity and anti-cardiolipin antibodies; whereas, the G allele was associated with lower frequencies of these clinical presentations. Relative expression levels were significantly lower in patients with the AA genotype [median: 18.86, interquartile range (IQR) 11.36-22.43, P = 0.002] than in those with the GG genotype (35.76, IQR: 19.33-49.71). As expected, we confirmed the A allele as a risk factor for SLE development in a Chinese population, in contrast, the G allele might be a protective factor against the pathogenic autoantibody formation and cutaneous manifestations in SLE patients.
In order to test the hypothesis that stratification of Mexican Modification of the Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI) simplifies the genetic study of SLE, we evaluated the genetic susceptibility to inflammation and defects in clearance of immune complexes among SLE patients in Taiwan. SLE phenotypes were stratified according to the MEX-SLEDAI scores into two subgroups (
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.