Ferreiro-Neira I, Calaza M, Alonso-Perez E, Marchini M, Scorza R, Sebastiani G D, Blanco F J, Rego I, Pullmann R, Pullmann R, Kallenberg C G, Bijl M, Skopouli F N, Mavromati M, Migliaresi S, Barizzone N, Ruzickova S, Dostal C, Schmidt R E, Witte T, Papasteriades C, Kappou-Rigatou I, Endreffy E, Kovacs A, Ordi-Ros J, Balada E, Carreira P, Gomez-Reino J J, Gonzalez A
Laboratorio Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain.
Genes Immun. 2007 Jul;8(5):429-38. doi: 10.1038/sj.gene.6364407. Epub 2007 Jun 14.
Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10(-17)) and protection (rs729302, P<10(-6)). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5' side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.
干扰素调节因子5（IRF5）基因的遗传变异会影响系统性红斑狼疮（SLE）的易感性。然而，这种关联很复杂且尚未完全明确。我们获取了14个欧洲样本集，共有1383例SLE患者和1614例对照，以更好地明确不同IRF5变异体的作用。研究了11个多态性，包括9个标签单核苷酸多态性（SNP）和2个额外的功能性多态性。两个标签SNP显示出独立且相反的关联：易感性（rs10488631，P<10^(-17)）和保护性（rs729302，P<10^(-6)）。单倍型分析表明，由rs10488631的次要等位基因确定的易感性单倍型可能是由于三个IRF5功能性多态性之间的上位性。这些多态性决定了mRNA表达增加、一个具有不同外显子1的剪接变体以及外显子6中更长的富含脯氨酸区域。这一结果很显著，因为这三个多态性中没有一个单独具有独立作用。保护性与这些多态性无关，似乎位于基因的5'端。总之，我们的结果通过明确区分由独立多态性引起的保护性和易感性，有助于理解IRF5基因座在SLE易感性中的作用。此外，我们发现了已知功能性多态性之间存在上位性导致易感性效应的证据。
