Tsai L-J, Hsiao S-H, Tsai L-M, Lin C-Y, Tsai J-J, Liou D-M, Lan J-L
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Tissue Antigens. 2008 Feb;71(2):114-26. doi: 10.1111/j.1399-0039.2007.00975.x. Epub 2007 Dec 6.
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.
对几种人类自身免疫性疾病的遗传学研究表明，16号染色体的着丝粒周围区域可能含有一个自身免疫修饰基因。我们推测钠依赖性葡萄糖共转运蛋白基因SLC5A11就是这样一个基因，因此可能与免疫相关基因相互作用。在此，这一假设在系统性红斑狼疮（SLE）多基因效应的遗传学评估中得到了验证。我们采用病例对照候选基因关联方法。选择了八个参与炎症、自身抗体产生和清除的免疫相关基因[白细胞介素1受体拮抗剂（IL1RN）、白细胞介素1-β（IL1-β）、肿瘤坏死因子-α（TNF-α）、淋巴毒素-α（LTA）、肿瘤坏死因子配体超家族成员6（TNFSF6）、程序性细胞死亡1（PDCD1）、C2和补体成分4（C4）]进行研究。比较了病例组和对照组中每个候选基因的基因型和等位基因频率。通过重新分析具有相关症状的基因型数据对结果进行分层。最后，采用改进的计算数据挖掘方法在大数据集中分析表型。在频率分析中，只有IL1-β与SLE显著相关。分层分析显示，除TNFSF6和C4外，SLC5A11与其他免疫相关基因之间与SLE症状存在显著关联。SLC5A11与低C4（TNF-α也是如此）、抗史密斯抗体（抗Sm）（C2也是如此）、浆膜炎和脱发显著相关。最后
