Protein c polymorphisms useful as an indicator of patient outcome

Abstract

The invention provides methods and kits for obtaining a prognosis for a patient having or at risk of developing an inflammatory condition. The method generally comprises determining a protein C promoter genotype of a patient for a polymorphism in the protein C promoter region of the patient, comparing the determined genotype with known genotypes for the polymorphism that correspond with the ability of the patient to recover from the inflammatory condition and identifying patients based on their prognosis. The invention also provides for methods of identifying other polymorphisms that correspond with the ability of the patient to recover from the inflammatory condition.

1 . A method for determining a prognosis for a human subject having, or at risk of developing, an inflammatory condition, the method comprising determining a genotype of said human subject at a polymorphic site in the subject's protein C gene at position 1386, 2583 or 3920 in SEQ ID NO: 1, wherein said genotype is indicative of the subject's ability to recover from the inflammatory condition which is SIRS, sepsis or septic shock, and wherein the relationship between the nucleotides at positions 1386, 2583 or 3920 and the prognosis for recovering from SIRS, sepsis or septic shock is as follows:
 (a) for SIRS, sepsis, or septic shock:
 (i) sense strand 1386TT homozygote or antisense strand 1386AA homozygote is prognostic of a decreased ability to recover; 
 (ii) sense strand 1386CC homozygote or antisense strand 1386GG homozygote is prognostic of an increased ability to recover; 
 (iii) sense strand 2583AA homozygote or antisense strand 2583TT homozygote is prognostic of a decreased ability to recover; 
 (iv) sense strand 2583TT homozygote or antisense strand 2583AA homozygote is prognostic of an increased ability to recover; 
 (v) sense strand 3920TT homozygote or antisense strand 3920AA homozygote is prognostic of a decreased ability to recover; and 
 (vi) sense strand 3920CC homozygote or antisense strand 3920GG homozygote is prognostic of an increased ability to recover; 
   (b) for septic SIRS:
 (i) sense strand 1386TC heterozygote or antisense strand 1386AG heterozygote is prognostic of an increased ability to recover compared to that of the 1386TT homozygote and a decreased ability to recover compared to that of the 1386CC homozygote; 
 (ii) sense strand 2583AT heterozygote or antisense strand 2583TA heterozygote is prognostic of an increased ability to recover compared to that of the 2583AA homozygote and a decreased ability to recover compared to that of the 2583TT homozygote; and 
 (iii) sense strand 3920TC heterozygote or antisense strand 3920AG heterozygote is prognostic of an increased ability to recover compared to that of the 3920TT homozygote and a decreased ability to recover compared to that of the 3920CC homozygote. 
   
     
     
         2 . The method of  claim 1 , further comprising determining the sequence of protein C of the human subject. 
     
     
         3 . The method of  claim 1 , wherein the genotype is determined using a nucleic acid sample from the human subject. 
     
     
         4 . The method of  claim 3 , which further comprises the step of obtaining the nucleic acid sample from the human subject. 
     
     
         5 . The method of  claim 1 , wherein said genotype is determined using one or more of the following techniques:
 (a) restriction fragment length analysis;   (b) sequencing;   (c) hybridization;   (d) oligonucleotide ligation assay;   (e) ligation rolling circle amplification;   (f) 5′ nuclease assay;   (g) polymerase proofreading methods; and   (h) allele specific PCR.   
     
     
         6 . The method of  claim 1 , wherein the human subject is critically ill, and has a genotype prognostic of a decreased ability of recover from SIRS, sepsis or septic shock and from severe cardiovascular or respiratory dysfunction present in SIRS, sepsis or septic shock. 
     
     
         7 . The method of  claim 1 , wherein the human subject is critically ill, and has a genotype prognostic of an increased ability of recover from SIRS, sepsis or septic shock and from mild cardiovascular or respiratory dysfunction present in SIRS, sepsis or septic shock. 
     
     
         8 . The method of  claim 1 , wherein the inflammatory condition is SIRS. 
     
     
         9 . The method of  claim 1 , wherein the inflammatory condition is sepsis. 
     
     
         10 . The method of  claim 1 , wherein the inflammatory condition is septic shock.