Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis.

Abstract

SummaryRecent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-oL. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P <0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-[3 gene, especially in females (RR = 9.5; P <0.001) compared with males (RR = 4; P <0.05). A significantly higher frequency (P <0.05) of allele 2 at the -308-basepair TNF-c~ gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P <0.05) even in the heterozygous condition. Because both the TNF-c~ and TNF-[3 polymorphisms have previously been linked with functional differences in TNF-oL levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-~x production.

Genetic analysis of multicase families of visceral leishmaniasis in northeastern Brazil: no major role for class II or class III regions of HLA

“…This would be consistent with a range of other infectious diseases, [11][12][13][14][15][16][17] including mucocutaneous leishmaniasis, 18 where allelic associations between disease and polymorphisms in the gene (TNFA) encoding TNF␣ or the closely linked gene (TNFB) encoding lymphotoxin A (LTA or TNF␤) have been observed. This may be functionally related to regulation of TNF␣ transcription by single nucleotide polymorphisms (SNPs) in the promoter region of TNFA.…”

Human V-ATPase gene can protect or predispose the host to pulmonary tuberculosis

“…Inflammation is finely regulated through a complex network of transcription factors and post-translational mechanisms. [40][41][42] It is therefore conceivable that pathogen susceptibility or resistance might also in part reflect differences in gene expression. A future challenge for genetic association studies of human diseases will be to identify polymorphisms in non-coding sequences.…”

Is there a future for TNF promoter polymorphisms?

“…SNPs in TNF have been found in association with several infectious diseases, including leishmaniasis, 77,78 scarring trachoma, 79 and a fatal course of meningococcal infections, 80 although a more recent study could not confirm this association. 81 In tuberculosis no evidence was found for linkage between susceptibility to disease per se and the TNF gene cluster in affected families.…”