囊狀纖維瘤患者的肺病嚴重程度在不同個體之間差異很大,，而且研究發(fā)現(xiàn)其嚴重程度有相當大的遺傳性，與引起原發(fā)病的CTFR（囊狀纖維瘤跨膜調控因子）突變的基因型無關,。
對超過300名囊狀纖維瘤患者所做的基因組分析發(fā)現(xiàn),，嗜中性轉錄共調因子IFRD1是肺病的一個遺傳修飾因子，通過嗜中性效應物上的一個效應發(fā)揮作用,。這一發(fā)現(xiàn)表明,，IFRD1是囊狀纖維瘤的一個可能的藥物作用目標，有潛在臨床意義,，因為肺病是囊狀纖維瘤患者發(fā)病和死亡的主要原因,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 458, 1039-1042 (23 April 2009) | doi:10.1038/nature07811
Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease
YuanYuan Gu1, Isaac T. W. Harley1, Lindsay B. Henderson5, Bruce J. Aronow2, Ilja Vietor7, Lukas A. Huber7, John B. Harley8, Jeffrey R. Kilpatrick8, Carl D. Langefeld9, Adrienne H. Williams9, Anil G. Jegga2, Jing Chen2, Marsha Wills-Karp3, S. Hasan Arshad10, Susan L. Ewart11, Chloe L. Thio6, Leah M. Flick1, Marie-Dominique Filippi4, H. Leighton Grimes3, Mitchell L. Drumm12, Garry R. Cutting5, Michael R. Knowles13 & Christopher L. Karp1
1 Division of Molecular Immunology,
2 Division of Biomedical Informatics,
3 Division of Immunobiology, and,
4 Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA
5 McKusick-Nathans Institute of Genetic Medicine, and,
6 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
7 Biocenter, Division of Cell Biology, Innsbruck Medical University, Innsbruck A-6020, Austria
8 Arthritis & Immunology Program, Oklahoma Medical Research Foundation, and JK Autoimmunity Inc., Oklahoma City, Oklahoma 73104, USA
9 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA
10 The David Hide Asthma and Allergy Research Centre, Newport, Isle of Wight, PO30 5TG, UK
11 Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824, USA
12 Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA
13 Cystic Fibrosis–Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype1. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-B p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease—a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.
