An association of VNTR polymorphism in intron3 of IL-4 gene with susceptibility to typhoid fever in Khartoum State, Sudan

Manal A. Fadl, Mawada A. Aydarous, Canguan Mao, Afshan Yasmeen


Host genetic factors play a role in determining susceptibility to infectious diseases ofhumans. Polymorphisms in Interleukin 4 (IL-4), an anti-inflammatory cytokine thatregulates the balance between T helper (Th1) and Th2 immune responses, has beenreported to affect the risk of infectious and autoimmune diseases.

In this study we aimed to investigate the possible association of variable numberof tandem repeat (VNTR) polymorphism in intron3 of IL-4 with susceptibility totyphoid fever in Sudanese patients. We analyzed the 70 bp intron-3 VNTR repeatpolymorphism in 200 DNA samples obtained from patients with blood cultureconfirmedtyphoid fever and 200 samples from randomly selected healthy controlsfrom the same city area. The intronic VNTR polymorphism was genotyped using PCR,followed by agarose gel elec trophoresis. The result showed that the genotypes of thetarget VNTR polymorphism in both cases and controls were not deviated from Hardy-Weinberg equilibrium (X 2, df=3=6.468, P˃ 0.05 and X 2, df=1=0.07, P˃ 0.5 respectively).The observed difference of the R3R3 & R2R2 genotypes among cases and controls isnot statistically significant (P= 0.09 and P=0.46 respectively). However, a significantincrease in the 2R3R genotype frequency among cases compared to the controls wasobserved (P˂0.05), indicating that the heterozygote 2R3R of VNTR polymorphism ofIL4 might affect individual susceptibility to typhoid fever in our population.


Gene polymorphism; Khartoum; Sudan; typhoid fever; VNTR, IL-4 gene.

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Ali, S., Vollaard, A.M., Widjaja, S., Surjadi, C., van de Vosse, E. & van Dissel J.T. (2006) PARK

/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Clinical and

Experimental Immunology, 144:425-431.

Ali, S., Vollaard, A.M., Kremer, D., de Visser, A.W., Martina, C.A., Widjaja, S., Surjadi, C., Slagboom,

E., van de Vosse, E. & van Dissel, J.T. (2007) Polymorphisms in proinflammatory genes and

susceptibility to typhoid fever and paratyphoid fever, 27(4):271-279.

Cantagrel, A., Navaux, F., Loubet-Lescoulié, P., Nourhashemi, F., Enault, G., Abbal, M., Constantin,

A., Laroche, M., Mazières, B. (1999) Interleukin-1beta, interleukin-1 receptor antagonist,

interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of

rheumatoid arthritis. Arthritis Rheumatology, 42:1093-1100.

Crump, J.A., Luby, S.P. & Mintz, E.D. (2004) The global burden of typhoid fever. Bull World Health

Organization, 82:346-353.

Dharmana, E., Joosten, I., Tijssen, H.J., Gasem, M.H., Indarwidayati, R., Keuter, M., Dolmans,

W.M., Van Der Meer, J.W. (2002) HLA-DRB1*12 is associated with protection against complicated

typhoid fever, independent of tumour necrosis factor alpha. European Journal of Immunogenetics,


Dunstan, S.J., Stephens, H.A., Blackwell, J.M., Duc, C.M., Lanh, M.N., Dudbridge, F., Phuong,

C.X., Luxemburger, C., Wain, J., Ho, V.A., Hien, T.T., Farrar, J. & Dougan, G. (2001) Genes

of the class II and class III major histocompatibility complex are associated with typhoid fever in

Vietnam. Journal of Infectious Diseases, 183:261-268.

Dunstan, S.J., Nguyen, T.H., Rockett, K., Forton, J., Morris, A.P., Diakite, M., Mai, N.L., Le,

T.P., House, D., Parry, C.M., Ha, V., Nguyen, T.H., Dougan, G., Tran, T.H., Kwiatowski, D.

& Farrar, J.J. (2007) A TNF region haplotype offers protection from typhoid fever in Vietnamese

patients. Human Genetics, 122(1):51-61.

Fadl, M.A., Miller, N., Mohamed, H., Elhassan, E., Ibrahim, M.E. & Blackwell, J.M. (2011) 5q34-

: One of the visceral leishmaniasis susceptibility loci demonstrated by a Genome wide search in

Sudanese population. Sudan Medical Monitor, 6(3):253-257.

Gervaziev, Y.V., Kaznacheev, V.A. & Gervazieva, V.B. (2006) Allelic polymorphisms in the interleukin-4

promoter regions and their association with bronchial asthma among the Russian population,


Hue, N.T., Lanh, M.N., Phuong, L.T., Ha Vinh, Chinh, N.T., Hien, T.T., Hieu, N.T., Farrar, J.J.,

Dunstan, S.J. (2009) Toll-Like Receptor 4 (TLR4) and Typhoid Fever in Vietnam. Plos One,


Leal, L.M., Moss, D.W., Kuhn, R., Muller, W. & Liew, F.Y. (1993) Interleukin-4 transgenic mice

of resistant background are susceptible to Leishmania major infection. European Journal of

Immunology, 23:566-569.

Luzia, H., Carvalho, Sano, G., Julius, C.R., Hafalla, Morrot, A., Maria A., Curotto de Lafaille &

Zavala, F. (2002) IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell

responses against malaria liver stages. Nature Medicine, 8:166-70.

Miller, N.E., Fadl, M.A., Mohamed, H.S., Elzein, A., Jamieson, S., Cordell, H.J., Peacock, C.S.,

Fakiola, M., Raju, M., Khalil, E.A., Elhassan, A., Musa, A.M., Ibrahim, M.E. & Blackwell, J.

M. (2007) Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 that

control visceral leishmaniasis in The Sudan. PLoS Genetics, 3(5):679-688.

Mohamed, H.S., Ibrahim, M.E., Miller, E.N., Peacock, C.S., Khalil, E.A., Cordell, H.J., Howson,

J.M., El Hassan, A.M., Bereir, R.E. & Blackwell, J.M. (2003) Genetic susceptibility to visceral leishmaniasis in the Sudan: linkage and association with IL4 and IFNGR1. Genes and Immunity,


Mout, R., Willemze, R. & Landegent, J.E. (1991) Repeat polymorphisms in the interleukin-4 gene

(IL4). Nucleic Acids Research, 19(13):3763.

Nakayama, E.E., Hoshino, Y., Xin, X., Liu, H., Goto, M. & Watanabe, N. (2000) Polymorphism in

the interleukin-4 promoter affects acquisition of human immunodeficiency virus type 1 syncytiuminducing

phenotype. Journal of Virology, 74(12):5452-5459.

Romagnani, S. (1995) Biology of human TH1 and TH2 cells. Journal of Clinical Immunology, 15(3):121-

Roy, S., McGuire, W., Mascie-Taylor, C.G., Saha, B., Hazra, S.K., Hill, A.V. & Kwiatkowski, D.

(1997) Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy.

The Journal of Infectious Diseases, 176(2):530-532.

Sadick, M.D., Heinzel, F.P., Holaday, B.J., Pu, R.T., Dawkins, R.S. & Locksley, R.M. (1990) Cure of

murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent,

interferon gamma-independent mechanism. Journal of Experimental Medicine, 171:115-127.

Uzonna, J.E. & Bretscher, P.A. (2001) Anti-IL-4 antibody therapy causes regression of chronic lesions

caused by medium-dose Leishmania major infection in BALB/c mice. European Journal of

Immunology, 31:3175-184.

Verra, F., Luoni, G., Calissano, C., Troye-Blomberg, M., Perlmann, P., Perlmann, H., Arca, B.,

Sirima, B.S., Konate, A., Coluzzi, M., Kwiatkowski, D. & Modiano, D. (2004) IL4-589C/T

polymorphism and IgE levels in severe malaria. Acta Tropica, 90(2):205-209.

Vidyarani, M., Selvaraj, P., Prabhu, S., Jawahar, M.S., Adhilakshmi, A.R. & Narayanan, P.R. (2006)

Interferon gamma (IFNγ) & interleukin-4 (IL-4) gene variants & cytokine levels in pulmonary

tuberculosis. Indian Journal of Medical Researches, 124:403-410.

Wattavidanage, J., Carter, R., Perera, K.L., Munasingha, A., Bandara, S., McGuinness, D.,

Wickramasinghe, A.R., Alles, H.K., Mendis, K.N. & Premawansa, S. (1999) TNFalpha*2

marks high risk of severe disease during Plasmodium falciparum malaria and other infections in Sri

Lankans. Clinical and Experimental Immunology, 115(2):350-355.


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