Distribution of D543N NRAMP1 polymorphism in tuberculosis patients from Kupang, east region of Indonesia

Trevino A. Pakasi; Ani Melani; Aulia Bramantyo; Ikhwanuliman Putera; Ikrar Syahmar; Elvina Karyadi; Edhyana Sahiratmadja

doi:10.13181/mji.v21i3.501

Authors

Trevino A. Pakasi
Ani Melani
Aulia Bramantyo
Ikhwanuliman Putera
Ikrar Syahmar
Elvina Karyadi
Edhyana Sahiratmadja

DOI:

https://doi.org/10.13181/mji.v21i3.501

Keywords:

D543N NRAMP1 polymorphism, eastern part of Indonesia, Kupang, tuberculosis

Abstract

Background: Natural resistance associated macrophage protein (NRAMP) is a proton/ divalent cation transporter which play a role in iron trafficking in the phagosomes. Variations in NRAMP1 gene have been reported to be associated with susceptibility to tuberculosis (TB) because Mycobacterium tuberculosis (MTb), the causative agent of TB, compete with its host to uptake iron for its metabolism. The study aimed to describe the polymorphism of NRAMP among TB patients in Kupang, East Nusa Tenggara.

Methods: This is a case-control study, cases were pulmonary TB, new patients, aged 15-55 years with sputum smear positive for acid fast bacili. Control were surrounding neighbours without symptoms and history of TB. All demographic information and blood sample were taken for polymorphism. PCR/RFLP method was performed to explore whether single nucleotide polymorphism D543N of NRAMP1 gene is associated with susceptibility to TB.

Results: The study involved 64 pulmonary TB patients and 51 healthy controls. We observed a significant different in the distribution of NRAMP1 genotypes frequencies between TB patients and healthy controls (p = 0.014). Moreover, D543N polymorphism gave significant association only in male subjects. Though the numbers of the subjects are limited, D543N NRAMP1 polymorphism in endemic region in Kupang, the eastern part of Indonesia, seems to be associated with the susceptibility to TB. This is in contrary to studies reported in other part of Indonesia: i.e from west part (Jakarta, Bandung) and central part (Makassar). The population from Kupang may similar genetic background as African population, as Mycobacterium infected in population from Kupang is mostly Mycobacterium africanum. Increasing the number of subjects may enhance the power of the study and possibility to meet Hardy-Weinberg Equilibrium to detect the true associations of this polymorphism in susceptibility to TB.

Conclusion: There was a significant difference of polymorphism NRAMP1 which more pronounced among male subjects, however this has not yet fulfilled the Hardy-Weinberg equilibrium. (Med J Indones. 2012;21:160-5)

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References

Schaible UE, Kaufmann SH. Ironand microbial infection.Nat Rev Microbiol. 2004;2(12):946-53.

McDermidJM, Prentice AM. Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin andNRAMP1(SLC11A1) on host-pathogen interactions in tuberculosis and HIV.Clin Sci (Lond). 2006;110(5):503-24.

Merza M, Farnia P, Anoosheh S, Varahram M, Kazampour M, Pajand O, et al. The NRAMPI, VDR and TNF-alpha gene polymorphisms in Iranian tuberculosis patients: the study on host susceptibility. Braz J Infect Dis. 2009;13(4):252-6.

Bellamy R, Ruwende C, Corrah T, McAdam KP, Whittle HC, Hill AV. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med. 1998;338(10):640-4.

GaoPS,Fujishima S,Mao XQ,Remus N,Kanda M,Enomoto T,et al. Genetic variants of NRAMP1 and active tuberculosis in Japanese populations. International TuberculosisGenetics Team. Clin Genet.2000;58(1):74-6.

Liu W, Cao WC, Zhang CY, Tian L, Wu XM, Habbema JD, et al. VDR and NRAMP1 gene polymorphisms in susceptibility to pulmonary tuberculosis among the Chinese Han population: a case-control study. Int J Tuberc Lung Dis.2004;8(4):428-34.

Ma X, Dou S, Wright JA, Reich RA, Teeter LD, El Sahly HM, et al. 5’ dinucleotide repeat polymorphism of NRAMP1 and susceptibility to tuberculosis among Caucasian patients in Houston, Texas. Int J Tuberc Lung Dis. 2002;6(9):818-23.

Søborg C, Andersen AB, Madsen HO, Kok-Jensen A, Skinhøj P, Garred P. Natural resistance-associated macrophage protein 1 polymorphisms are associated with microscopy-positive tuberculosis. J Infect Dis. 2002;186(4):517-21.

El Baghdadi J, Remus N, Benslimane A, El Annaz H, Chentoufi M, Abel L, et al. Variants of the human NRAMP1 gene and susceptibility to tuberculosis in Morocco. Int J Tuberc Lung Dis. 2003;7(6):599-602.

Niño-Moreno P, Portales-Pérez D, Hernández-Castro B, Portales-Cervantes L, Flores-Meraz V, Baranda L, et al. P2X7 and NRAMP1/SLC11 A1 gene polymorphisms in Mexican mestizo patients with pulmonary tuberculosis.Clin Exp Immunol. 2007;148(3):469-77.

Hsu YH, Chen CW, Sun HS, Jou R, Lee JJ, Su IJ. Association of NRAMP1 gene polymorphism with susceptibility to tuberculosis in Taiwanese aboriginals. J Formos Med Assoc. 2006;105(5):363-9

Vejbaesya S, Chierakul N, Luangtrakool P, Sermduangprateep C. NRAMP1 and TNF-alpha polymorphisms and susceptibility in Thais. Respirology. 2007;12(2): 202-6

Delgado JC, Baena A, Thim S, Goldfeld AE. Ethnic-specific genetic associations with pulmonary tuberculosis. J Infect Dis. 2002;186(10):1463-8.

Sahiratmadja E, Wieringa FT, van Crevel R, de Visser AW, Adnan I, Alisjahbana B, et al. Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3’UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population. Br J Nutr. 2007;98(4):684-90.

Hatta M, Ratnawati, Tanaka M, Ito J, Shirakawa T, Kawabata M. NRAMP1/SLC11A1 gene polymorphisms and host susceptibility to Mycobacterium tuberculosis and M. leprae in South Sulawesi, Indonesia. Southeast Asian J Trop Med Public Health. 2010;41(2):386-94.

Li HT, Zhang TT, Zhou YQ, Huang QH, Huang J. SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis. Int J Tuberc Lung Dis. 2006;10(1):3-12.

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(9):1232-6.

Kim JH, Lee SY, Lee SH, Sin C, Shim JJ, In KH, et al. NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy. Int J Tuberc Lung Dis. 2003;7(4):370-5.

van Crevel R, Parwati I, Sahiratmadja E, Marzuki S, Ottenhoff TH, Netea MG, et al. Infection with Mycobacterium tuberculosis Beijing genotype strains is associated with polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis. J Infect Dis. 2009;200(11):1671-4.

World Health Organization. Worldwide prevalence of anaemia 1993–2005. Geneva: World Health Organization; 2008. ISBN978-92-4-159665-7.

Gruenheid S, Gros P. Genetic susceptibility to intracellular infection: NRAMP1, macrophage function, and divalent cations transport. Curr Opin Microbiol. 2000;3(1):43-8.

Kuhn DE, Baker BD, Lafuse WP, Zwilling BS. Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169. J Leukoc Biol. 1999;66(1):113-9.

Bloom BR, Small PM. The evolving relation between humans and Mycobacterium tuberculosis. N Engl J Med. 1998;338(10):677-8.

Nugraha J, Anggraini R. NRAMP1 polymorphism and susceptibility to lung tuberculosis in Surabaya, Indonesia. Southeast Asian J Trop Med Public Health. 2011;42(2):338-41.

Jin J, Sun L, Jiao W, Zhao S, Li H, Guan X, et al. SLC11A1 (formerly NRAMP1) gene polymorphisms associated with pediatric tuberculosis in China. Clin Infect Dis. 2009;48(6):733-8.

Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA. 1994;271(9):698–702.

Sahiratmadja E, Wieringa FT, van Crevel R, de Visser AW, Adnan I, Alisjahbana B, et al. Iron deficiency and NRAMP1 polymorphisms (INT4, D543N, and 3’UTR) do not contribute to severity of anemia in tuberculosis in Indonesian population. Br J Nutr. 2007;98(4):684-90.

Karafet TM, Hallmark B, Cox MP, Sudoyo H, Downey S, Lansing JS, et al. Major east-west division underlies Y chromosome stratification acrossIndonesia.Mol Biol Evol. 2010;27(8):1833-44.

Farnia P, Pajand O, Anoosheh S, et al. Comparison of Nramp1 gene polymorphism among TB health care workers and recently infected cases; assessment of host susceptibility. Tanaffos. 2008;7(1):19-24.

ParwatiI, van Crevel R, Sudiro M, Alisjahbana B, Pakasi T, Kremer K, et al. Mycobacterium tuberculosis population structures differ significantly on two Indonesian Islands.J Clin Microbiol.2008;46(11):3639-45.