HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA–forming microsatellite

Abstract

Agenetic basis for resistance to infection by intracellular pathogens was proposed several years ago.1-6 This concept was confirmed upon the positional cloning of the dominant autosomal gene Ity/Lsh/Bcg based on its ability to confer on inbred mice an innate resistance to infection by diverse intracellular pathogens.7 These include Salmonella typhimurium, 2 Leishmania donovani,3 and some species of Mycobacterium such as M bovis5 and M intracellulare.8 Targeted ablation of Ity/Lsh/ Bcg9 or allelic exchange in susceptible mice10 confirmed its requirement for resistance to infection. Ity/Lsh/Bcg encodes the phagocyte-specific solute carrier 11a1 protein Slc11a1 (formerly Nramp1),11-13 which restricts pathogen replication by inducing the expression of major histocompatibility complex (MHC) class II molecules, cytokines (eg, TNF ), and chemokines.14 SLC11A1/Slc11a1 belongs to a family of polytopic membrane proteins whose functions include divalent cation acquisition in mammals (DCT1/DMT1/NRAMP2),15 taste perception in the fruit fly (malvolio),16 and stress signal transduction in plants (EIN2).17 In mice, a single nonsynonymous mutation in Slc11a1 codon 169 determines resistance (Gly169) or susceptibility (Asp169) to intracellular bacterial and leishmanial infections.7 Compared with susceptible mice, macrophages from mice that are resistant to infection also show increased oxidative burst and expression of the MHC class II transactivator CIITA, and I-A antigen.18-21 Human genetic variation and disease association studies have undergone a paradigm shift from mutation detection in susceptibility genes to whole-genome scans for single nucleotide polymorphisms (SNPs)22 and transcriptional analyses of the cognate genes to better understand the evolution of complex traits such as disease risk. Cis and/or trans-acting regulatory variation accounts greatly for quantitative differences in such traits.23-31 Evidence suggests that structural variation in candidate susceptibility genes (eg, due to mutations) cannot wholly account for such differences. In most cases, there are no identifiable mutations within such genes, including SLC11A1,32,33 yet there are demonstrable phenotypic differences (eg, in resistance to infection). No mutations occur in (human) SLC11A1 analogous to the functional coding region mutation in the murine ortholog, despite the apparent association of the gene with a variety of infectious and inflammatory diseases, including tuberculosis and rheumatoid arthritis (reviewed by Blackwell et al14,34). Disease association was found between specific (noncoding) polymorphic loci that included introns and microsatellites in both the 5 and 3 regions of the gene.32,35 Population-based Submitted December 20, 2006; accepted June 13, 2007. Prepublished online as Blood First Edition paper, July 2, 2007; DOI 10.1182/blood-2006-12-063289. The online version of this article contains a data supplement. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 USC section 1734.