Natural resistance-associated macrophage protein 1 gene polymorphisms in thalassemia patients with tuberculosis infection

Main Article Content

Mohammad Ghozali
Sari Puspa Dewi
Reni Ghrahani
Ani Melani Maskoen
Lelani Reniarti
Edhyana Sahiratmadja
Tri Hanggono Achmad

Abstract

that needs regular blood transfusions leading to accumulation of iron in the cells. This iron overload level in macrophage might cause intracellular bacteria, particularly Mycobacterium tuberculosis (MTB) to multiply. Polymorphisms in natural resistance-associated macrophage protein 1 (NRAMP1), a metal transporter across the phagosome membrane, play important role in regulating iron, which is also needed by MTB. Increased iron in thalassemia patients may have an increased potential risk for TB.
Objective To compare natural resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms (INT4, D543N, and 3’UTR) in thalassemia patients with and without tuberculosis (TB) infection.
Methods A cross-sectional measurement of NRAMP1 genetic polymorphisms was performed in pediatric thalassemia patients with TB (n=40) and without TB (n=50). Iron status including serum iron, total iron-binding capacity (TIBC), and ferritin, was compared between the two groups. The NRAMP1 genetic polymorphisms were analysed using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Allelic and genotypic distributions of each polymorphism were assessed for possible associations with TB infection.
Results Mean serum iron and TIBC in thalassemia patients with TB were higher compared to thalassemia patients without TB (mean serum: 166.26 vs. 134.92 μmol/L, respectively; P=0.026) and (mean TIBC: 236.78 vs. 195.84 μmol/L, respectively; P=0.029). In thalassemia patients with TB, we observed significantly higher frequency of the C allele in INT4 (10% vs. 2%, respectively; OR=5.44; 95%CI 1.1 to 26.4; P=0.02) and the TGTG deletion allele (78.8% vs. 51%, respectively; OR=3.56; 95%CI 1.83 to 6.9; P=0.0002) in 3’UTR polymorphisms than in thalassemia patients without TB. There were no significant 

differences in distributions of the A allele between TB and non-TB groups (16.3% vs. 15%, respectively; P=0.84) or the GA genotype (32.5% vs. 30%, respectively; P=0.79) in D543N.
Conclusion The NRAMP1 polymorphisms are known to be associated with major gene susceptibility to TB, and in our thalassemia patients this association is even more pronounced.

Article Details

How to Cite
1.
Ghozali M, Dewi SP, Ghrahani R, Maskoen AM, Reniarti L, Sahiratmadja E, Achmad TH. Natural resistance-associated macrophage protein 1 gene polymorphisms in thalassemia patients with tuberculosis infection. PI [Internet]. 19Jul.2016 [cited 21Jul.2019];56(2):84-. Available from: https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/114
Section
Pediatric Hemato-Oncology
Author Biography

Mohammad Ghozali, Department of Biochemistry and Molecular Biology, Universitas Padjadjaran Medical School/Dr. Hasan Sadikin General Hospital, Bandung, West Java.

 

 

 

 

 

Received 2016-07-19
Accepted 2016-07-19
Published 2016-07-19

References

1. Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol. 2004;2:946-53.
2. Schaible UE, Collins HL, Priem F, Kaufmann SH. Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J Exp Med. 2002;196:1507-13.
3. UN WHO. Global Tuberculosis Report 2007. United Nation World Health Organization (WHO); 2007. p.249.
4. Kumar R, Sagar C, Sharma D, Kishor P. Beta-globin genes: mutation hot-spots in the global thalassemia belt. Hemoglobin. 2015;39:1-8.
5. Khan FA, Fisher MA, Khakoo RA. Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis. 2007;11:482-7.
6. Gangaidzo IT, Moyo VM, Mvundura E, Aggrey G, Murphree NL, Khumalo H, et al. Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis. 2001;184:936-9.
7. U.S. Department of Health and Human Services; Centers for Disease Control and Prevention National Center for HIV/AIDS VH, STD, and TB Prevention; Division of Tuberculosis Elimination. Latent tuberculosis infection: a guide for primary health care providers. Atlanta: CDC; 2013. p.5.
8. Ottenhoff TH, Verreck FA, Hoeve MA, van de Vosse E. Control of human host immunity to mycobacteria. Tuberculosis. 2005;85:53-64.
9. Lounis N, Truffot-Pernot C, Grosset J, Gordeuk VR, Boelaert JR. Iron and Mycobacterium tuberculosis infection. J Clin Virol. 2001;20:123-6.
10. Olakanmi O, Schlesinger LS, Ahmed A, Britigan BE. Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis. J Biol Chem. 2002;277:49727-34.
11. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol. 2001;19:93-129.
12. Olakanmi O, Schlesinger LS, Britigan BE. Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages. J Leukoc Biol. 2007;81:195-204.
13. Klopfleisch R, Olias P. The pathology of comparative animal models of human haemochromatosis. J Comp Pathol. 2012;147:460-78.
14. Saito H. Metabolism of Iron Stores. Nagoya J Med Sci. 2014;76:235-54.
15. Indonesia UPPIDAI. Pedoman Nasional Tuberkulosis Anak. Jakarta: Kementerian Kesehatan Republik Indonesia; 2005. p.23.
16. Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. New Engl J Med. 1998;338:640-4.
17. Porter JB. Pathophysiology of transfusional iron overload: contrasting patterns in thalassemia major and sickle cell disease. Hemoglobin. 2009;33:S37-45.
18. Cronje L, Bornman L. Iron overload and tuberculosis: a case for iron chelation therapy. Int J Tuberc Lung Dis. 2005;9:2-9.
19. Marx JJ. Iron and infection: competition between host and microbes for a precious element. Best Pract Res Clin Haematol. 2002;15:411-26.
20. Botella H, Stadthagen G, Lugo-Villarino G, de Chastellier C, Neyrolles O. Metallobiology of host-pathogen interactions: an intoxicating new insight. Trends Microbiol. 2012;20:106-12.
21. Bellamy R. Susceptibility to mycobacterial infections: the importance of host genetics. Genes Immun. 2003;4:4-11.
22. Canonne-Hergaux F, Gruenheid S, Govoni G, Gros P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc Assoc Am Physicians. 1999;111:283-9.
23. Bellamy R. NRAMP1 and susceptibility to tuberculosis. Int J Tuberc Lung Dis. 2002;6:747.
24. Zhang W, Shao L, Weng X, Hu Z, Jin A, Chen S, et al. Variants of the natural resistance-associated macrophage protein 1 gene (NRAMP1) are associated with severe forms of pulmonary tuberculosis. Clin Infect Dis. 2005;40:1232-6.
25. Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J Exp Med. 2000;192:1237-48.