Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease

Abstract

Relatively little is known about the human genetics of susceptibility to common diseases caused by bacterial pathogens. Tuberculosis, caused by Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. So far, genetic studies of tuberculosis susceptibility have largely been focused on adult patients despite the fact that tuberculosis is highly prevalent among children. To study the host genetic component of pediatric tuberculosis susceptibility, we enrolled 184 ethnically diverse families from the Greater Houston area with at least one child affected by pediatric tuberculosis disease. Using a family-based control design, we found allelic variants of the natural resistance-associated macrophage protein gene 1 (NRAMP1) (alias SLC11A1) significantly associated with tuberculosis disease in this pediatric patient population [P = 0.01; odds ratio = 1.75 (95% confidence interval, 1.10-2.77)]. The association of NRAMP1 with pediatric tuberculosis disease was significantly heterogeneous (P = 0.01) between simplex [P <0.0008; odds ratio = 3.13 (1.54-6.25)] and multiplex families (P = 1), suggesting an interplay between mechanisms of genetic control and exposure intensities. In striking contrast to previous studies in the adult population, we observed that the common alleles of NRAMP1 polymorphisms were risk factors for pediatric tuberculosis disease. To explain the different direction of allelic association between adult and pediatric disease, we hypothesize that NRAMP1 influences the speed of progression from infection to tuberculosis disease.

Fig. 1.

Schematic presentation of the NRAMP1 candidate gene and intragenic location of gene polymorphisms. The genomic distance spanned by NRAMP1 in kilobase pairs (kb), the exon numbers, the translational initiation (ATG), and termination sequences (Stop) and the location of distinct gene polymorphisms with respect to the exon-intron organization are given on the left side of the diagram. Designation of gene polymorphisms either adopted names already established in the literature or followed standard nomenclature rules (51). The type of polymorphism-microsatellite repeat, SNP, insertion/deletion polymorphism (INS/DEL), together with a simple polymorphism alias as well as the identity and frequency of the common allele, are also indicated. Finally, the number of families comprising at least one parent heterozygous for the polymorphisms, i.e., a parent for which preferential allele transmission can be monitored, is given. P values indicating evidence for distortion of allele transmissions are given for the Family Based Association Test (FBAT) (33) and the Reconstruction-Combined TDT (RC-TDT) (35) analytical procedures.

Fig. 2.

LD pattern in the Hispanic population between pairs of SNPs spanning the NRAMP1 gene and its upstream genomic region. The NRAMP1 3′ region is located on the right end of the schematic chromosome line indicated on top of the graph. Consequently, the NRAMP1 gene orientation is in the 3′ to 5′ orientation from right to left. The telomere of chromosome 2q is located toward the right. Names of polymorphisms used for the LD matrix of pairs of markers are given, and their chromosomal locations are indicated by solid lines. Haplotype blocks according to Gabriel et al. (38) are indicated, and names of markers that are part of haplotype blocks are indicated in bold. Each square represents the magnitude of pairwise LD. Each pairwise D′ measure is shown as D′ × 10² within the corresponding square. Squares without D′ written on them represent D′of 1.0. Black squares indicate pairwise LD that is strong [lower confidence interval (CI), 0.7, upper CI >0.92], light-gray squares represent intermediate strength LD, and white squares represent weak LD.