Rahimov Fedik, Marazita Mary L, Visel Axel, Cooper Margaret E, Hitchler Michael J, Rubini Michele, Domann Frederick E, Govil Manika, Christensen Kaare, Bille Camille, Melbye Mads, Jugessur Astanand, Lie Rolv T, Wilcox Allen J, Fitzpatrick David R, Green Eric D, Mossey Peter A, Little Julian, Steegers-Theunissen Regine P, Pennacchio Len A, Schutte Brian C, Murray Jeffrey C
Department of Pediatrics, University of Iowa, 2182 ML, S Grand Ave, Iowa City, Iowa 52242, USA.
Nat Genet. 2008 Nov;40(11):1341-7. doi: 10.1038/ng.242. Epub 2008 Oct 5.
Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2alpha and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.
此前我们已经表明，非综合征性唇裂伴或不伴腭裂（NSCL/P）与IRF6（干扰素调节因子6）中的单核苷酸多态性（SNP）密切相关。在此，我们通过多物种序列比较，在新发现的IRF6增强子中鉴定出一个常见的SNP（rs642961，G>A）。在患有NSCL/P的家庭中，尤其是那些患有唇裂但不伴有腭裂的家庭中，A等位基因显著过度传递（P = 1×10⁻¹¹）。此外，A等位基因存在剂量效应，AG基因型唇裂的相对风险为1.68，AA基因型为2.40。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）试验表明，风险等位基因破坏了转录因子AP-2α的结合位点，在小鼠中的表达分析将增强子活性定位到颅面和肢体结构。我们的研究结果将IRF6和AP-2α置于同一发育途径中，并在一个调控元件中鉴定出一个高频变异体，该变异体对一种常见的复杂疾病有很大影响。
