Abstract—Currently only a small fraction of the proteins encoded in the human genome serve as pharmaceutical targets. Genome-wide association studies are a powerful tool to uncover new genetic loci responsible for predisposition to complex diseases, such as autoimmune disorders. However, further work is still required to identify causative single-nucleotide polymorphisms (SNPs) which directly mediate the disease risk at these loci, and to determine their target genes. These genes can be located millions base pairs away from the regulatory SNPs. Here, by using bioinformatic tools and databases, we identified five intergenic autoimmunity-associated polymorphisms with high probability of being causative, for which the target genes are still unknown. We tested their ability to influence gene expression using luciferase reporter system. The polymorphism rs6832151 affected the reporter expression in the CEM human T-cell line upon the highest enhancer activity. Target genes of this SNP could be further identified by introducing point mutations to the genome and comparison of transcriptomes of the derivative cell sublines carrying alternative alleles of rs6832151.

摘要-目前，人类基因组中编码的蛋白质中只有一小部分充当药物靶标。全基因组关联研究是发现导致易患复杂疾病（例如自身免疫性疾病）的新基因位点的有力工具。然而，仍需要进一步的工作来鉴定直接介导这些基因座的疾病风险的致病性单核苷酸多态性（SNP），并确定其靶基因。这些基因可以位于距调节SNP数百万个碱基对的位置。在这里，通过使用生物信息学工具和数据库，我们确定了五种基因间自身免疫相关的多态性，这些多态性具有高致病性，而目标基因仍然未知。我们使用萤光素酶报告系统测试了它们影响基因表达的能力。rs6832151多态性以最高的增强子活性影响了CEM人T细胞系中报告基因的表达。通过将点突变引入基因组并比较带有rs6832151替代等位基因的衍生细胞亚系的转录组，可以进一步鉴定该SNP的靶基因。