SLC11A1 (formerly NRAMP1) polymorphisms associated with multidrug-resistant tuberculosis

Takahashi, Kosuke; Hasegawa, Yoshinori; Abe, Tomoji; Yamamoto, Tomoko; Nakashima, Kiyotaka; Imaizumi, Kazuyoshi; Shimokata, Kaoru

doi:10.1016/j.tube.2007.08.008

Cited by 18 publications

(15 citation statements)

References 22 publications

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“…A study of Vietnamese subjects detected an association between the C allele of TLR2 597T/C and TB caused by East Asian/Beijing genotype M. tuberculosis strains (41). Genetic variations in the 3=-UTR and the D543N SNP of SLC11A1 (NRAMP1) were significantly associated with susceptibility to infection by M. tuberculosis Beijing strains in Indonesian TB patients (241) and with the incidence of MDR-TB cases in Japan (223), which suggests an influence of bacterial genotype/ phenotype on host innate immunity. To what extent these same variants also interact with other M. tuberculosis strains remains to be tested.…”

Section: Factors That Influence the Functions Of Innate Immune Gene Pmentioning

confidence: 99%

Innate Immune Gene Polymorphisms in Tuberculosis

2012

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ABSTRACTTuberculosis (TB) is a leading cause worldwide of human mortality attributable to a single infectious agent. Recent studies targeting candidate genes and “case-control” association have revealed numerous polymorphisms implicated in host susceptibility to TB. Here, we review current progress in the understanding of causative polymorphisms in host innate immune genes associated with TB pathogenesis. We discuss genes encoding several types of proteins: macrophage receptors, such as the mannose receptor (MR, CD206), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN, CD209), Dectin-1, Toll-like receptors (TLRs), complement receptor 3 (CR3, CD11b/CD18), nucleotide oligomerization domain 1 (NOD1) and NOD2, CD14, P2X7, and the vitamin D nuclear receptor (VDR); soluble C-type lectins, such as surfactant protein-A (SP-A), SP-D, and mannose-binding lectin (MBL); phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), RANTES, and CXCL10; and other important innate immune molecules, such as inducible nitric oxide synthase (iNOS) and solute carrier protein 11A1 (SLC11A1). Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations. This apparent variability is probably accounted for by evolutionary selection pressure as a result of long-term host-pathogen interactions in certain regions or populations and, in part, by lack of proper study design and limited knowledge of molecular and functional effects of the implicated genetic variants. Finally, we discuss genomic technologies that hold promise for resolving questions regarding the evolutionary paths of the human genome, functional effects of polymorphisms, and corollary impacts of adaptation on human health, ultimately leading to novel approaches to controlling TB.

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Section: Factors That Influence the Functions Of Innate Immune Gene Pmentioning

confidence: 99%

Innate Immune Gene Polymorphisms in Tuberculosis

2012

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“…Additionally, a Taiwanese aboriginal casecontrol study revealed that individuals possessing one of the three polymorphism of the SLC11A1 gene have higher susceptibility to tuberculosis, with those who are heterozygous for the INT4 polymorphism being at greatest risk [6]. Similar findings have also been reported in Chinese, Korean, Japanese, Iranian, AfricanAmerican and Caucasian populations [7][8][9][10][11][12]. In bovine studies, a genomic region of the 3'UTR of the SLC11A1 cDNA gene sequence is associated with natural resistance against bTB.…”

Section: Introductionmentioning

confidence: 54%

“…Previous studies on the INT4 polymorphism (G>C change in intron 4) have shown that exon 4a is encoded by an Alu element within intron 4, resulting in a truncated and hence non-functional NRAMP1 [26]. In supporting the importance of the human SLC11A1 gene in host defense mechanisms against tuberculosis [8], previous studies support associations between INT4 polymorphisms and bacilli growth (which may affect outcomes in pulmonary tuberculosis) [7,10,21,27]. Furthermore, variations in the promoter in linkage disequilibrium with INT4 may regulate the level of normal SLC11A1 mRNA transcribed, and/or the ratio of normal to alternatively spliced product (for example, exon 4a-which was found to be expressed in vivo -would introduce a termination codon in the downstream exon 5, resulting in a severely truncated protein) [26].…”

Section: Discussionmentioning

confidence: 87%

“…This transporter -which functions as part of the innate immune responseplays a key role in inhibiting proliferation of Mycobacterium tuberculosis (M. tuberculosis), through its involvement in acidification of phagosomes [5]. The relationships between various polymorphisms in the human SLC11A1 gene and mycobacterial diseases have been explored, including INT4 (single nucleotide G>C change in intron 4, 469+14G/C, rs3731865), D543N (conservative single base G>A substitution at codon 543, resulting in a change to asparagine from aspartic acid), and 3'UTR TGTG (a deletion in the 3' untranslated region, 1729+55del) [6][7][8][9][10]. Additionally, a Taiwanese aboriginal casecontrol study revealed that individuals possessing one of the three polymorphism of the SLC11A1 gene have higher susceptibility to tuberculosis, with those who are heterozygous for the INT4 polymorphism being at greatest risk [6].…”

Section: Introductionmentioning

confidence: 99%

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Relationship of Bovine SLC11A1 (Formerly NRAMP1) Polymorphisms to the Risk of Bovine Tuberculosis in Holstein Cattle

Cheng

Huang²,

Tsai³

2015

J Veterinar Sci Technol

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Many studies suggest significant genetic variation in the resistance of cattle and humans to infection with Mycobacterium bovis, the causative agent of zoonotic tuberculosis. The natural resistance associated macrophage protein 1 (NRAMP1), encoded by the SLC11A1 gene, plays a key role in the immunological control of a broad spectrum of infectious agents. The aim of the present study was to investigate the influence of single nucleotide polymorphisms (SNPs) of the SLC11A1 gene on bovine tuberculosis (bTB) susceptibility. We genotyped the SLC11A1 gene in 60 bTB-infected Holstein cows and 90 healthy control animals. The influence in the exon 4 and intron 4 regions of SLC11A1 genetic variations on bTB susceptibility was subsequently investigated by association analysis. Our finding demonstrated that the g.107117166A>G and g.107117369C>T polymorphisms of the SLC11A1 gene associated with bTB in Holstein cattle. The susceptibility of cattle with the g.107117166A>G genotype compared with the GG genotype was 3.40 (95% CI: 1.10-10.51; p=0.048) fold higher. The g. 107117166A>G SNP located in the exon 4 of the SLC11A1 gene and the functional consequence was missense. The deduced amino acid sequence for the protein product revealed an alanine to threonine conversion at position 96, which may affect initiation of protein synthesis and disrupt normal NRAMP1 function that protects animals against mycobacterial infection. The other susceptibility of cattle with the g.107117369C>T genotype compared with the TT genotype was 0.26 (95% CI: 0.12-0.56; p=0.001) fold lower. The g.107117369C>T polymorphism, located in the intron 4 of the SLC11A1 gene, may affect elements that control transcription and splicing of the NRAMP1 leading to affect pathophysiological characteristics in tuberculosis. This is the first report showing that the g. 107117166A>G and g.107117369C>T polymorphisms may contribute to SLC11A1-mediated bTB susceptibility.

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“…A single gene that is not associated with susceptibility to TB will show an association if combined with other genes [38,39]. Besides, gene-agent interaction showed association of a certain host gene with a certain strain of Mycobacterium tuberculosis [40,41].…”

Section: Discussionmentioning

confidence: 99%

Is There Any Impact of VDR Gene Polymorphism in Bataks Ethnic to Have Tuberculosis?

Siregar¹,

Sinaga²

2017

JHS

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Abstract:The active metabolite of vitamin D activates macrophages and results in the restriction of growth of Tuberculosis (TB) pathogen M. tuberculosis. The effect of vitamin D is achieved through binding to the Vitamin D Receptor (VDR), which ultimately produces the antimicrobial peptide Cathelicidin. Matched case-control study with 76 pulmonary tuberculosis Indonesian Batak ethnic patients and 76 healthy normal control were completed. Genetic polymorphisms of VDR gene were analysed using PCR and RFLP. The genotype frequencies of ApaI were AA 10.6%, Aa 44.7%, aa 44.7% for the control group and AA 10.6%, Aa 43.4%, aa 46% for the PTB patients. For the FokI genotype the frequencies were FF 39.5%, Ff 44.7%, ff 15.8% for the control group and FF 35.5%, Ff 55.3%, ff 9.2% for the PTB patients. In these two genotypes there were no significant differences found between the control group and the PTB patients (P > 0.05). Besides, there genotypic frequencies were in agreement with the Hardy-Weinberg Equilibrum (P > 0.05). However, for the BsmI genotype frequencies, BB 2.6%, Bb 23.7% and bb 73.7% for the control group and BB 0%, Bb 68.4%, bb 31.6% for the PTB patients, there was a significant association found with PTB; the bb genotype is correlated with a decreased risk for PTB (OR 0.22, 95% CI: 0.11-0.45). ApaI and FokI polymorphisms of VDR gene do not appear to be responsible for host susceptibility to pulmonary tuberculosis in the Indonesian Batak ethnic population but BsmI polymorphism had association with host resistant to PTB.

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SLC11A1 (formerly NRAMP1) polymorphisms associated with multidrug-resistant tuberculosis

Cited by 18 publications

References 22 publications

Innate Immune Gene Polymorphisms in Tuberculosis

Innate Immune Gene Polymorphisms in Tuberculosis

Relationship of Bovine SLC11A1 (Formerly NRAMP1) Polymorphisms to the Risk of Bovine Tuberculosis in Holstein Cattle

Is There Any Impact of VDR Gene Polymorphism in Bataks Ethnic to Have Tuberculosis?

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