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

Abstract

BackgroundIt 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.Methods198 CF patients and 130 control subjects were genotyped for both TNF-α–308GA and LT-α + 252AG polymorphisms.ResultsThe carriers of the TNF-α–308A allele more frequently had asthma as compared to patients homozygous for the TNF-α–308 G allele. In 9 of 108 (8.3%) of LTα + 252AA carriers, tuberculosis infection has been documented, whereas there was no case of tuberculosis among patients, either homozygous or heterozygous for LTα +252 G alleles (p = 0.01). We never observed virus hepatitis among LTα + 252GA carriers. The genotypes TNF-α–308GG – LT-α + 252AA and TNF-α–308GA – LT-α + 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-α–308GA or LT-α + 252GG. In addition the carriers of such genotypes demonstrated a higher risk of osteoporosis development (p values were 0.011 and 0.017, respectively).ConclusionsThe carriers of genotypes, which are associated with higher TNF-α 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-α production showed a higher frequency of tuberculosis infection.

Overexpression of RANKL in osteoblasts: a possible mechanism of susceptibility to bone disease in cystic fibrosis

“…Clinical data have reported that CF complications with TNF gene polymorphisms coupled with high serum TNF production are associated with decreased bone density [58]. Consistently, our experiments with TNF-stimulated CF osteoblasts showed both enhanced production of RANKL and defective production of OPG and thus support a link between the high levels of TNF and osteoclastogenesis.…”

Visualization and quantitative analysis of extrachromosomal telomere-repeat DNA in individual human cells by Halo-FISH

“…ECTR DNA is only one of many species of extrachromosomal mammalian DNA, some of which are found in healthy cells from normal tissues. These extrachromosomal DNA species can be restricted to specific cell types such as the T- and B-excision circles generated during V(D)J recombination in lymphocytes ( 42 ), while others, including non-repetitive microDNAs and repetitive elements derived from satellite DNA and 5S ribosomal DNA, can be found in healthy cells from multiple organs ( 3 , 4 ). On the other hand, certain extrachromosomal DNA species are associated with disease.…”

The associations of TNF‐α gene polymorphisms with bone mineral density and risk of osteoporosis: A meta‐analysis

“…However, as the heterogeneity among these studies was relatively high ( I 2 = 53%), we next conducted sensitivity analysis by successively excluding each observation. As shown in Figure B, after excluding those secondary osteoporosis patients (CF), we found that the GG genotype significantly increased the risk of osteoporosis (OR = 0.63, 95% CI: 0.51‐0.77, P < 0.0001, I 2 = 31%), indicating that this polymorphism may be a promising genetic marker, especially for predicting the risk of essential osteoporosis.…”

“…1 In addition, osteoporosis and related fragility fractures are also common complications in patients with other diseases, such as cystic fibrosis (CF), Crohn's disease and rheumatoid arthritis (RA). [2][3][4] However, despite the fact that the pathogenetic mechanisms of this Suo-Chao Fu, Ping Wang and Ming-Xing are contributed equally to this work. disease were intensively investigated, factors that contribute to the development of osteoporosis are rather complicated and yet need to be further defined.…”