title: The predictive value of IL28B rs12979860, rs11881222 and rs8099917 polymorphisms and IP-10 in the therapeutic response of Egyptian genotype 4 patients.
abstract: Interleukin-28B (IL28B) polymorphisms have previously been reported to be strongly associated with spontaneous and treatment-induced HCV viral clearance.
  
  
  OBJECTIVE
  To assess the impact of four different IL28B polymorphisms and their haplotype combination and interferon-c inducible protein 10 (IP-10) in response to treatment in Egyptian genotype 4 patients.
  
  
  METHODS
  159 HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. The following polymorphisms rs12979860, rs11881222, rs8103142 and rs8099917 and rs80803142 of Il-28 were known to be associated with the sustained virological response. They were genotyped using the TaqMan assay. IP-10 was assessed by Eliza.
  
  
  RESULTS
  The data indicated that all SNPs are within the Hardy-Weinberg Equilibrium (HWE) except for rs8103142 (p=6.255(-9)), therefore it was excluded from the study since it deviates from HWE-P. The CC, AA and TT genotypes of rs12979860, rs11881222 and rs8099917 were the more frequent genotypes among the responders at RVR, EVR, ETR and SVR, respectively. The frequency of CC, CT, and TT genotype was 46.4%, 38.1% and 15.5% among responders of RVR, and was 46.9%, 45.9% and 7.2 among responders of SVR for rs12979860, respectively. The relapse rate was 18.0% and 16.0 % during EVR and ETR, while the response rate was 52.8%, 58.5%, 59.7% and 61.6% after 4, 12, 48 and 72 weeks of treatment. The transient virological response (TVR) was 6.9% among HCV patients. The results showed that the odds ratio and 95% CI of HCV genotype 4 patients to have a better sustained response to treatment (SVR) was 2.92, (1.83-4.68, p=2.01(-5)), 2.89 (1.79-4.70, p=2.53(-5)), and 2.73 (0.21-0.65, p=0.0007) for those with the major allele "C" of rs12979860, the "A" allele of rs11881222, and the "T" allele of rs8099917, respectively. Furthermore, the positive predictive value (PPV) of the major homozygous alleles for SVR with better response to therapy was in the following order: 78.69%, 68.42%, and 32.14% with a positive likelihood ratio of 1.95, 1.25, and 0.86 for rs12979860, rs11881222 and rs8099917, respectively. The haplotype formed between the 3 studied SNPs (rs12979860, rs11881222 and rs8099917) showed that two haplotypes (TGG and TGT) increased the probability of a poor response to therapy, but the CAT haplotype had the opposite effect. Multinomial logistic regression analysis revealed that the viral load and rs12979860 are the only significant actors involved in the efficacy of the treatment response among the cohort study. In addition, patients with SVR had significantly lower values of IP-10 than non-responder patients (NR), with a P-value<=0.001.
  
  
  CONCLUSIONS
  In genotype 4 cases, the IL28B SNPs rs12979860 rs8099917, and rs11881222 are the strongest predictors of a response, while IP-10 is a strong negative biomarker of a response. Accounting for this factor is important in the individualization of treatment and enhances the degree of predictiveness of the IL28 polymorphism in the final treatment outcome. The frequent distribution of C, A and T alleles of IL28 polymorphism are higher among TVR, which may reflect sensitivity to prolonged course.
authors.affiliation: Gastroenterology and Hepatology Department, Hamad Hospital, Doha, Qatar. mod2002@qatar-med.cornell.edu
authors.forename: Moutaz
authors.initials: M
authors.lastname: Derbala
authors.forename: Nasser M
authors.initials: NM
authors.lastname: Rizk
authors.forename: Saad
authors.initials: S
authors.lastname: Al-Kaabi
authors.forename: Anil
authors.initials: A
authors.lastname: John
authors.forename: Manik
authors.initials: M
authors.lastname: Sharma
authors.forename: Nazeeh
authors.initials: N
authors.lastname: El-dweik
authors.forename: Rafie
authors.initials: R
authors.lastname: Yakoob
authors.forename: Fuad
authors.initials: F
authors.lastname: Pasic
authors.forename: Muneera
authors.initials: M
authors.lastname: Almohanadi
authors.forename: Khalid
authors.initials: K
authors.lastname: Alejji
authors.forename: Abdulatif
authors.initials: A
authors.lastname: Abdelmola
authors.forename: Mohamed
authors.initials: M
authors.lastname: Butt
mesh_terms: D000328:Adult; D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics*; D015331:Cohort Studies; D004534:Egypt; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006239:Haplotypes; D016174:Hepacivirus / Q000145:classification / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome; D000095022:Interferon Lambda
chemical_list: D054357:Chemokine CXCL10; D007372:Interferons; D007378:Interleukins; C114753:CXCL10 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
keywords: Genotype 4; HCV; IL28B polymorphis; IP 10