Graham Robert R, Kyogoku Chieko, Sigurdsson Snaevar, Vlasova Irina A, Davies Leela R L, Baechler Emily C, Plenge Robert M, Koeuth Thearith, Ortmann Ward A, Hom Geoffrey, Bauer Jason W, Gillett Clarence, Burtt Noel, Cunninghame Graham Deborah S, Onofrio Robert, Petri Michelle, Gunnarsson Iva, Svenungsson Elisabet, Rönnblom Lars, Nordmark Gunnel, Gregersen Peter K, Moser Kathy, Gaffney Patrick M, Criswell Lindsey A, Vyse Timothy J, Syvänen Ann-Christine, Bohjanen Paul R, Daly Mark J, Behrens Timothy W, Altshuler David
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6758-63. doi: 10.1073/pnas.0701266104. Epub 2007 Apr 5.
Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.
绘制与人类疾病相关的基因组区域的全基因组系统性研究正变得越来越可行。越来越多的努力将集中在识别导致疾病的特定功能变异上。识别因果变异的挑战包括需要全面确定遗传变异以及需要考虑多个因果等位基因的可能性。我们最近报告称，系统性红斑狼疮（SLE）的风险与干扰素调节因子5（IRF5）中的一个常见单核苷酸多态性（SNP）密切相关，并且该变异以一种可能为与SLE风险的可重复性关联提供功能解释的方式改变了剪接。在此，通过对SLE患者进行重测序和基因分型，我们发现了IRF5的三个功能等位基因的证据：先前描述的外显子1B剪接位点变异、外显子6中一个30bp的框内插入/缺失变异，该变异改变了富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的结构域区域，以及一个保守的聚腺苷酸加尾信号序列中的变异，该变异改变了3'非翻译区（UTR）的长度和IRF5 mRNA的稳定性。这三个变异的单倍型定义了至少三种不同程度的SLE风险。了解变异组合如何影响IRF5功能可能为SLE提供病因学和治疗方面的见解；更广泛地说，IRF5和SLE说明了同一基因的多个常见变异如何共同影响常见疾病的风险。
