Method for determining predisposition to pulmonary infection

Abstract

Provided herein are methods and materials for diagnosing a subject's predisposition for pulmonary infection in a CF subject by detecting a pulmonary infection genetic marker. Pulmonary infection markers have been identified in the IL-1 gene cluster and may be useful in predicting CF disease progression and assessing a CF subject's response to therapy.

We claim: 
     
         1 . A method for determining a cystic fibrosis subject's predisposition for pulmonary infection, comprising
 (a) providing a nucleic acid-containing sample obtained from a cystic fibrosis subject; and   (b) determining whether the sample comprises a pulmonary infection marker, wherein the marker is selected from the group consisting of rs1143639 256T , rs1143634 401A , rs2228139 301G , rs17561 256A , rs3917356 256C , rs1143633 401T , rs3917368 301T , rs4252019 501T , and rs2071374 301G  and   wherein the presence of the marker indicates that the subject has a predisposition for pulmonary infection.   
     
     
         2 . The method of  claim 1 , wherein the marker is detected by:
 (a) amplifying a nucleic acid comprising the marker; and   (b) detecting the amplified nucleic acids, thereby detecting the marker.   
     
     
         3 . The method of  claim 2 , wherein the marker is detected by sequencing. 
     
     
         4 . The method of  claim 2 , wherein the marker is amplified using a pair of primers comprising the sequences selected from the group consisting of SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36. 
     
     
         5 . The method of  claim 2 , wherein the amplified nucleic acids are detected by hybridizing an oligonucleotide probe to the amplified product. 
     
     
         6 . The method of  claim 5 , wherein the probe is labeled with a detectable label. 
     
     
         7 . The method of  claim 5 , wherein the probe is an oligonucleotide comprising a SNP selected from the group consisting of rs1143639 256T , rs1143634 401A , rs2228139 301G , rs17561 256A , rs3917356 256C , rs1143633  401T , rs3917368 301T , rs4252019 501T , and rs2071374 301G . 
     
     
         8 . The method of  claim 1 , wherein the presence of a marker selected from the group consisting of rs3917356 256C , rs1143633 401T , rs4252019 501T , rs1143639 256T  is diagnostic of the subject having a predisposition for severe pulmonary infection. 
     
     
         9 . The method of  claim 1 , wherein the presence of rs2071374 301G  is diagnostic of the subject having a predisposition for mild pulmonary infection. 
     
     
         10 . The method of  claim 1 , wherein the subject is female. 
     
     
         11 . The method of  claim 10 , wherein the presence of rs2228139 301G  or rs1143634 401A  is diagnostic of severe lung disease. 
     
     
         12 . The method of  claim 1 , wherein the subject is male. 
     
     
         13 . The method of  claim 12 , wherein the presence of rs17561 256A  is diagnostic of the male subject having a predisposition to severe pulmonary infection. 
     
     
         14 . The method of  claim 1 , wherein a gene selected from the group consisting of IL-1α, IL-1RN, IL-1R1, and IL-1β comprises the marker. 
     
     
         15 . The method of  claim 1 , wherein the pulmonary infection is associated with bacterial lung colonization. 
     
     
         16 . The method of  claim 15 , wherein the lung is colonized by a bacterium selected from the group consisting of  P. aeruginosa, S. aureus, H. influenzae, B. cepacia,  methicillin-resistant  S. aureus, S. maltophilia,  and  A. xylosoxidans.    
     
     
         17 . A method of treating a subject identified in  claim 1 , comprising administering an anti-infection agent to the subject. 
     
     
         18 . The method of  claim 17 , wherein the anti-infection agent is an anti-inflammatory. 
     
     
         19 . The method of  claim 18 , wherein the anti-inflammatory is an IL1 blocker. 
     
     
         20 . The method of  claim 19 , wherein the IL1 blocker is selected from the group consisting of rilonacept, anakinra, and Zn-protoporphyrin (ZnPP). 
     
     
         21 . The method of  claim 17 , wherein the anti-infection agent is an antibiotic. 
     
     
         22 . The method of  claim 21 , wherein the antibiotic is selected from the group consisting of an aminoglycoside, amoxicillin, levofloxacin, dicloxacillin, cephalexin, amoxicillin/clavulanate, erythromycin, clarithromycin, azithromycin, clindamycin, cefuroxime axetil, cefprozil, cefixime, cefpodoxime proxetil, loracarbef, ciprofloxacin, tobramycin, colistin, trimethoprim/sulfamethoxazole, doxycycline, minocycline, cefazolin, nafcillin, vancomycin, β-lactam, ceftazidime, ticarcillin, piperacillin, imipenem, meropenem, aztreonam, an aminoglycoside, amikacin, merpenem, ceftazidime, chloramphenicol, ticarcillin/clavulanate, aztreonam, imipenem, a polypeptide antibiotic, and meropenem. 
     
     
         23 . A kit comprising:
 (a) nucleic acid sample collecting means;   (b) means for determining the presence of a pulmonary infection marker in a nucleic acid; and   (c) a control sample comprising polymorphic DNA selected from the group consisting of rs1143639 256T , rs1143639 256C , rs1143634 401A , rs1143634 401G , rs2228139 301G , rs2228139 301C , rs17561 256A , rs17561 256C , rs3917356 256C , rs3917356 256T , rs1143633 401T , rs1143633 401C , rs3917368 301T , rs3917368 301C , rs4252019 501T , rs4252019 501C , and rs2071374 301G , and rs2071374 301T .