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TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression.

ABSTRACT: BACKGROUND: It is well known that the disease progression in cystic fibrosis (CF) patients may be diverse in subjects with identical mutation in CFTR gene. It is quite possible that such heterogeneity is associated with TNF-? and/or LT-? gene polymorphisms since their products play a key role in inflammation. The aim of the study was to investigate the possible roles of TNF gene polymorphisms in CF disease phenotype and progression. METHODS: 198 CF patients and 130 control subjects were genotyped for both TNF-?-308GA and LT-? + 252AG polymorphisms. RESULTS: The carriers of the TNF-?-308A allele more frequently had asthma as compared to patients homozygous for the TNF-?-308 G allele. In 9 of 108 (8.3%) of LT? + 252AA carriers, tuberculosis infection has been documented, whereas there was no case of tuberculosis among patients, either homozygous or heterozygous for LT? +252 G alleles (p = 0.01). We never observed virus hepatitis among LT? + 252GA carriers. The genotypes TNF-?-308GG - LT-? + 252AA and TNF-?-308GA - LT-? + 252AG were unfavorable with regard to liver disease development (both p < 0.05). It was also shown that neutrophil elastase activity was higher in sputum specimens from high TNF producers with genotypes TNF-?-308GA or LT-? + 252GG. In addition the carriers of such genotypes demonstrated a higher risk of osteoporosis development (p values were 0.011 and 0.017, respectively). CONCLUSIONS: The carriers of genotypes, which are associated with higher TNF-? production, demonstrated increased frequency of asthma, higher levels of neutrophil elastase, and decrease of bone density. On the contrary, the carriers of genotypes associated with low TNF-? production showed a higher frequency of tuberculosis infection.

SUBMITTER: Shmarina G

PROVIDER: S-EPMC3565881 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression.

Shmarina Galina G Pukhalsky Alexander A Petrova Nika N Zakharova Ekaterina E Avakian Lucine L Kapranov Nikolai N Alioshkin Vladimir V

Journal of translational medicine 20130123

<h4>Background</h4>It is well known that the disease progression in cystic fibrosis (CF) patients may be diverse in subjects with identical mutation in CFTR gene. It is quite possible that such heterogeneity is associated with TNF-α and/or LT-α gene polymorphisms since their products play a key role in inflammation. The aim of the study was to investigate the possible roles of TNF gene polymorphisms in CF disease phenotype and progression.<h4>Methods</h4>198 CF patients and 130 control subjects ...[more]

PMID: 23343370

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Project description:Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection.We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for DeltaF508, and categories of "severe" (cases) or "mild" (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV(1)) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR < or =0.5 or >1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children's Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed.SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value <0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status.Our findings suggest that IL1beta is a clinically relevant modulator of CF lung disease.

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TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression.

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TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression.

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