Association of Single-Nucleotide Polymorphism in the Hepcidin Promoter Gene with Susceptibility to Extrapulmonary Tuberculosis

摘要

Background: Hepcidin is a 25-amino acid peptide produced by the liver in response to inflammation and iron overload. It is encoded by the hepcidin antimicrobial peptide (HAMP) gene and plays a key role in innate immunity. Previous studies have reported that a -582A>G polymorphism in the HAMP promoter (HAMP-P) affects hepcidin expression, causing susceptibility to various bacterial and viral pathogens. However, it is not known whether the HAMP-P -582A>G polymorphism is associated with tuberculosis (TB) susceptibility. Aims: The objective of the current study was to examine the relationship between the HAMP-P -582A>G polymorphism and TB susceptibility in a Chinese Han population. Methods: Han Chinese subjects examined included 500 pulmonary TB, 386 extrapulmonary TB, and 600 healthy control subjects. We analyzed correlations between the hepcidin promoter -582A>G polymorphism and disease susceptibility and then examined the regulatory effects of the -582A>G variant on hepcidin production in CD14+ monocyte cultures stimulated with lipoarabinomannan derived from Mycobacterium tuberculosis. Results: Our findings indicate that the HAMP-P -582A>G polymorphism (rs10421768) is associated with susceptibility to extrapulmonary TB, but not pulmonary TB. CD14+ monocytes from individuals with the rs10421768 GG genotype secreted significantly less hepcidin in response to M. tuberculosis lipoarabinomannan compared with cells from individuals with either the AA or AG genotypes. Conclusions: The G allele of the HAMP-P -582A>G gene may play a critical role in TB susceptibility.