Nat Gene：基因变异可导致囊性纤维化病人胎儿出现肠梗阻

近日，来自北卡罗来纳大学等处的研究者发现，基因组上某些区域的变异容易使得囊性纤维化病人在怀孕期间，胎儿出现肠梗阻。这项研究报告于4月1日刊登在了国际著名杂志Nature Gentics上，研究者们识别出了和胎粪性肠梗阻（meconium ileus，MI）相关的遗传变异，MI是一种肠梗阻疾病，通常需要紧急的外科手术才能治疗，可以导致其它健康问题发病比率的持续增长。

粗略估计，MI可以影响15%-20%的囊性纤维化病人（CF），可以使病人全身结痂尤其是肺部和胰腺，CF病人身上所有拷贝的基因都存在着突变，这种基因常常编码囊性纤维化跨膜传导调节蛋白（CFTR）。

对于超过3700个CF病人进行全基因组相关性研究（GWAS）后，研究者通过分离细胞外和细胞内环境，发现了细胞膜上存在非囊性纤维化跨膜传导调节蛋白（CFTR）的遗传变异。更具体来说，这些基因的突变对小肠末端的离子转运会产生的一定的反应。小肠细胞的这些突变容易使得CF病人在母体子宫内演变成为胎粪性肠梗阻。

研究者的研究发现为理解MI的分子致病机理提供了一定的帮助，另外也提供了一种在母体子宫内的可能治疗的方法。研究者Knowles表示，这将为我们理解CF病人离子转运蛋白突变在机体内所扮演的角色提供一定的分子基础，而且我们可以将这种分子机制更为广泛的应用。

doi:10.1038/ng.2221
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Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Lei Sun1, 2, 18 Johanna M Rommens3, 4, 18 Harriet Corvol5, 6 Weili Li1, 7 Xin Li7 Theodore A Chiang7 Fan Lin3 Ruslan Dorfman3 Pierre-François Busson8 Rashmi V Parekh3 Diana Zelenika9 Scott M Blackman10 Mary Corey7 Vishal K Doshi11 Lindsay Henderson11 Kathleen M Naughton11 Wanda K O'Neal12 Rhonda G Pace12 Jaclyn R Stonebraker12 Sally D Wood12 Fred A Wright13 Julian Zielenski3 Annick Clement5, 6 Mitchell L Drumm14, 15 Pierre-Yves Boëlle6, 8 Garry R Cutting10, 11 Michael R Knowles12 Peter R Durie16, 17 Lisa J Strug1, 7

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10−12 at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10−9 at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.