患有囊肿性纤维化的个体患者具有较高的绿脓杆菌感染风险,而绿脓杆菌感染又与长期性肺部疾病加重和存活率降低有关。最新一期《自然—遗传学》(nature genetics )上的一项报告解析出若干与绿脓杆菌感染症的易感性有关的遗传变异。
为了鉴定出影响绿脓杆菌感染风险的宿主遗传因子,Michael Bamshad、 Mary Emond等人使用了一种极端表现型研究设计方案,选择那些处于表现型分布两端的患者,并结合了外显子测序手段。作为美国国立心肺血液研究所(NHLBI)的外显子测序计划(ESP)的一部分,此次研究对43名初步感染绿脓杆菌的患者以及48名从未感染过绿脓杆菌的年长患者进行了外显子测序。结果发现,DCTN4中的数个变异与肿囊性纤维化患者体内的绿脓杆菌的首次空气传染、慢性感染以及黏液型绿脓杆菌存在关联。他们继续对696名肿囊性纤维化患者进行检测,验证了上述发现。(生物谷Bioon.com)
doi:10.1038/ng.2344
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Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis
Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders1. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large2. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles3. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.