Polymorphisms in the Gene That Encodes the Iron Transport Protein Ferroportin 1 Influence Susceptibility to Tuberculosis

Background. We studied the association between iron intake and polymorphisms in the iron transporter gene SLC40A1 and the risk of tuberculosis. Methods. We compared iron intake, the frequency of SLC40A1 mutations, and interactions among these variables among 98 tuberculosis patients and 125 controls in KwazuluNatal, South Africa. Results. Four SLC40A1 single-nucleotide polymorphisms (SNPs) were associated with an increased risk of tuberculosis and 1 SNP with reduced risk. We also found a gene‐environment interaction for 4 nonexonic SNPs and iron intake. Conclusions. This pilot study demonstrated an association between polymorphisms in SLC40A1 and tuberculosis and provided evidence of an interaction between dietary iron and SLC40A1. One third of the world’s population is infected with Mycobacterium tuberculosis (M. tuberculosis), but only a minority develops active tuberculosis. Excess iron has been implicated as a risk factor for tuberculosis in both in vitro and clinical studies. Restriction of iron in culture media curtails growth of M. tuberculosis, and iron loading in mice enhances bacterial growth in lung and spleen [1, 2]. Iron supplementation has been shown to lead to increased morbidity and mortality in patients, and autopsies show that death from tuberculosis can be accompanied by splenic iron overload [3]. Recognizing the physiological importance of iron availability for mycobacterial growth [4], we hypothesized that functional variants of the iron transporter, ferroportin 1 (FPN1), may affect host susceptibility to tuberculosis. ‘‘African iron overload syndrome’’ is characterized by increased iron and serum ferritin, but unlike ‘‘classic’’ HFE hemochromatosis, excess iron is located in macrophages rather than parenchyma. Although this syndrome had been ascribed to intake of traditional African beer brewed in nongalvanized steel drums, an autosomal-dominant form of iron overload has been described in which iron accumulation is restricted to reticuloendothelial cells [5]. This entity is now believed to be identical to ‘‘ferroportin disease,’’ which is associated with polymorphisms in SCL40A1, the gene that encodes the iron exporter FPN1 [6].