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Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults

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Abstract

Polymorphic variability in immune response genes, such as IL12B, encoding the IL-12p40 subunit is associated with susceptibility to severe malaria in African populations. Since the role of genetic variation in conditioning severe malaria in Thai adults is largely unexplored, the functional association between IL12B polymorphisms [i.e. IL12Bpro (rs17860508) and IL12B 3′ UTR T/G (rs3212227)], severe malaria and cytokine production was examined in patients with Plasmodium falciparum infections (n = 355) recruited from malaria endemic areas along the Thai–Myanmar border in northwest Thailand. Circulating IL-12p40 (p = 0.049) and IFN-γ (p = 0.051) were elevated in patients with severe malaria, while only IL-12p40 was significantly higher in severe malaria patients with hyperparasitaemia (p = 0.046). Carriage of the IL12Bpro1.1 genotype was associated with enhanced severity of malaria (OR, 2.34; 95% CI, 0.94–5.81; p = 0.066) and hyperparasitaemia (OR, 3.42; 95% CI, 1.17–9.87; p = 0.025) relative to the IL12Bpro2.2 genotype (wild type). Individuals with the IL12Bpro1.1 genotype also had the lowest IL-12p40 (p = 0.002) and the highest IFN-γ (p = 0.004) levels. Construction of haplotypes revealed that carriage of the IL12Bpro-2/3′ UTR-T haplotype was associated with protection against severe malaria (OR, 0.51; 95% CI, 0.29–0.90; p = 0.020) and reduced circulating IFN-γ (p = 0.06). Thus, genotypic and haplotypic variation at IL12Bpro and IL12B 3′ UTR in this population influences susceptibility to severe malaria and functional changes in circulating IL-12p40 and IFN-γ levels. Results presented here suggest that protection against severe malaria in Thai adults is associated with genotypic variants that condition enhanced IL-12p40 and reduced IFN-γ levels.

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Abbreviations

SNP:

Single nucleotide polymorphism

IL-12:

Interleukin-12

IL-12p40:

40-kDa subunit of IL-12

IFN-γ:

Interferon gamma

IL12B :

Gene encoding 40-kDa subunit of IL-12, IL12B 3′ UTR:A → C SNP located in the 3′ untranslated region (UTR) at position 1188 of the IL12B gene

IL12Bpro:

A compound polymorphism involving a GC/TT transition combined with an AGAG micro-insertion within the promoter region of the IL12Bpro

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Acknowledgements

We wish to thank the late Professor Sornchai Looareesuwan, Department of Clinical Tropical Medicine and Hospital for Tropical Diseases, Mahidol University for providing blood samples and clinical data. We also thank his staff for assistance in blood collection and slide reading. We thank the patients for their kind participation in the study.

Authors’ contributions

SK, DJP and CP designed the study. CP collected blood samples, genotyped the IL12Bpro and IL12B 3′ UTR polymorphisms, participated in data analysis and writing of the manuscript. CO assisted in genotyping of IL12Bpro (rs17860508) polymorphisms, data analysis and writing of the manuscript. PT collected blood samples and determined the circulating IFN-γ levels. JT determined circulating IL-12p40 levels. TW assisted in genotyping of IL12B 3′ UTR polymorphisms and data analysis. DW and YM assisted in data analysis. SK and DJP financed the study, performed data analyses and co-wrote the manuscript. All authors have read and approved the final version of the manuscript.

Financial support

This study was supported by the Royal Golden Jubilee Ph.D. Program (PHD/0197/2549) of the Thailand Research Fund (CP and SK), the Commission on Higher Education of Thailand (CP), the National Institutes of Health [AI51305–06 (DJP) and TW05884–06 (DJP)] and the Faculty of Tropical Medicine, Mahidol University.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand

    Chintana Phawong, Piyatida Tangteerawatana, Jarinee Thongshoob, Yuvadee Mahakunkijcharoen & Srisin Khusmith

  2. Centre for Global Health Research, University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya

    Collins Ouma, Tom Were & Douglas Jay Perkins

  3. Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya

    Collins Ouma

  4. Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand

    Piyatida Tangteerawatana

  5. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Duangrurdee Wattanasirichaigoon

  6. Global and Geographic Medicine, Division of Infectious Diseases, University of New Mexico School of Medicine, MSC10-5550, Albuquerque, NM, 87131-0001, USA

    Douglas Jay Perkins

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  1. Chintana Phawong
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  2. Collins Ouma
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  8. Douglas Jay Perkins
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Correspondence to Douglas Jay Perkins or Srisin Khusmith.

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Phawong, C., Ouma, C., Tangteerawatana, P. et al. Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults. Immunogenetics 62, 345–356 (2010). https://doi.org/10.1007/s00251-010-0439-y

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