Background Systemic lupus erythematosus (SLE) is an autoimmune disease in which genetic susceptibility contributes to immune dysregulation and increased disease risk. However, the specific mechanisms by which these SNPs influence gene and protein expression and ultimately affect disease pathology remain unclear. Thus, this study integrated genotype and protein expression results to thoroughly investigate the influence of genetic variation on the immune mechanisms underlying systemic lupus erythematosus (SLE). Methods A total of 38 SLE patients and 34 healthy controls were included in this study. The cell percentage and expression level of CD28, CTLA-4, and PD-1 on the CD3+CD4+ cells were assessed by flow cytometry, in which phytohemagglutinin, interleukin-7, and interleukin-2 were used to stimulate cells to detect CTLA-4 and PD-1. Associations between SNP genotypes and protein expression or cell proportions were subsequently evaluated using the Mann-Whitney U test, with significance at p = 0.017. Finally, the data were integrated with our previous functional analyses of SNPs to elucidate the role of co-stimulatory gene variants in SLE. Results The GT genotype of the CD28 rs1879877 was associated with increased CD3⁺CD28⁺ expression (p = 0.017) exclusively in patients with SLE. Additionally, the TT genotype of the CTLA4 rs733618 was associated with increased cell percentage (p = 0.007 in SLE group and 0.011 in combined group), and the TT genotype of rs16840252 were associated with increased CTLA-4 expression (p = 0.004) in the resting status. Furthermore, the CC genotype of rs36084323 and the GG genotype of rs2227982 were associated with increased PD-1 expression in the SLE group (p = 0.014) and combined group (p = 0.002 and 0.001). Notably, rs36084323 and rs2227982 consistently correlated strongly with increased PD-1 expression after stimulation (p = 0.002 and 0.001). Conclusion These findings highlight that SNPs in the CTLA4 and PDCD1 genes act as general regulatory variants, while only CD28 rs1879877 appears to have an enhanced effect on CD28 expression specifically under the SLE disease condition. Additionally, the rs733618 and rs36084323 SNPs were associated with SLE and exhibited significant differences in transcriptional activity.

Deciphering the role of SNP variants of co-stimulatory genes in systemic lupus erythematosus: from genotype to protein expression

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2026年7月13日

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Ding-Ping Chen,
Gem Huai-Chueh Wu,
Wei-Tzu Lin,
Kuang-Hui Yu

摘要

Background

Systemic lupus erythematosus (SLE) is an autoimmune disease in which genetic susceptibility contributes to immune dysregulation and increased disease risk. However, the specific mechanisms by which these SNPs influence gene and protein expression and ultimately affect disease pathology remain unclear. Thus, this study integrated genotype and protein expression results to thoroughly investigate the influence of genetic variation on the immune mechanisms underlying systemic lupus erythematosus (SLE).

Methods

A total of 38 SLE patients and 34 healthy controls were included in this study. The cell percentage and expression level of CD28, CTLA-4, and PD-1 on the CD3⁺CD4⁺ cells were assessed by flow cytometry, in which phytohemagglutinin, interleukin-7, and interleukin-2 were used to stimulate cells to detect CTLA-4 and PD-1. Associations between SNP genotypes and protein expression or cell proportions were subsequently evaluated using the Mann-Whitney U test, with significance at p = 0.017. Finally, the data were integrated with our previous functional analyses of SNPs to elucidate the role of co-stimulatory gene variants in SLE.

Results

The GT genotype of the CD28 rs1879877 was associated with increased CD3⁺CD28⁺ expression (p = 0.017) exclusively in patients with SLE. Additionally, the TT genotype of the CTLA4 rs733618 was associated with increased cell percentage (p = 0.007 in SLE group and 0.011 in combined group), and the TT genotype of rs16840252 were associated with increased CTLA-4 expression (p = 0.004) in the resting status. Furthermore, the CC genotype of rs36084323 and the GG genotype of rs2227982 were associated with increased PD-1 expression in the SLE group (p = 0.014) and combined group (p = 0.002 and 0.001). Notably, rs36084323 and rs2227982 consistently correlated strongly with increased PD-1 expression after stimulation (p = 0.002 and 0.001).

Conclusion

These findings highlight that SNPs in the CTLA4 and PDCD1 genes act as general regulatory variants, while only CD28 rs1879877 appears to have an enhanced effect on CD28 expression specifically under the SLE disease condition. Additionally, the rs733618 and rs36084323 SNPs were associated with SLE and exhibited significant differences in transcriptional activity.