A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

Louise Randall, Enny Kenangalem, Daniel Lampah, Emiliana Tijitra, Esther Mwaikambo, Tjandra Handojo, Kim Piera, Zhen Zhen Zhao, Fabian de Labastida Rivera, Yonghong Zhou, Karli McSweeney, Lien Le, Fiona Amante, Ashraful Haque, Amanda Stanley, Tonia Woodberry, Ervi Salwati, Donald Granger, Maurine Hobbs, Ric PriceJ Brice Weinberg, Grant Montgomery, Nicholas Anstey, Christian Engwerda

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    Abstract

    Background

    Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.

    Methods

    An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.

    Results

    No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.

    Conclusions

    These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

    Original languageEnglish
    Article number302
    Pages (from-to)1-9
    Number of pages9
    JournalMalaria Journal
    Volume9
    DOIs
    Publication statusPublished - 29 Oct 2010

    Fingerprint

    Malaria
    Tumor Necrosis Factor-alpha
    Single Nucleotide Polymorphism
    Plasmodium falciparum
    Cerebral Malaria
    Lymphotoxin-alpha
    Haplotypes
    Population
    Genes
    Morbidity
    Mortality

    Cite this

    Randall, L., Kenangalem, E., Lampah, D., Tijitra, E., Mwaikambo, E., Handojo, T., ... Engwerda, C. (2010). A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults. Malaria Journal, 9, 1-9. [302]. https://doi.org/10.1186/1475-2875-9-302
    Randall, Louise ; Kenangalem, Enny ; Lampah, Daniel ; Tijitra, Emiliana ; Mwaikambo, Esther ; Handojo, Tjandra ; Piera, Kim ; Zhao, Zhen Zhen ; de Labastida Rivera, Fabian ; Zhou, Yonghong ; McSweeney, Karli ; Le, Lien ; Amante, Fiona ; Haque, Ashraful ; Stanley, Amanda ; Woodberry, Tonia ; Salwati, Ervi ; Granger, Donald ; Hobbs, Maurine ; Price, Ric ; Weinberg, J Brice ; Montgomery, Grant ; Anstey, Nicholas ; Engwerda, Christian. / A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults. In: Malaria Journal. 2010 ; Vol. 9. pp. 1-9.
    @article{97fc5ffc19494c16970383ff50b74536,
    title = "A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults",
    abstract = "BackgroundSevere malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.MethodsAn extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.ResultsNo associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.ConclusionsThese results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.",
    keywords = "lymphotoxin, lymphotoxin beta, tumor necrosis factor, LTB protein, human, TNF protein, human, tumor necrosis factor alpha, adult, article, brain malaria, child, chromosome 6, controlled study, disease severity, gene, gene linkage disequilibrium, gene locus, gene sequence, genetic susceptibility, genotype, haplotype, human, Indonesia, LTA gene, LTB gene, malaria falciparum, nonhuman, Plasmodium falciparum, preschool child, school child, single nucleotide polymorphism, tnf gene, genetic predisposition, genetics, immunology, Papua New Guinea, pathology, Adult, Child, Child, Preschool, Genetic Predisposition to Disease, Humans, Lymphotoxin-alpha, Lymphotoxin-beta, Malaria, Falciparum, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha",
    author = "Louise Randall and Enny Kenangalem and Daniel Lampah and Emiliana Tijitra and Esther Mwaikambo and Tjandra Handojo and Kim Piera and Zhao, {Zhen Zhen} and {de Labastida Rivera}, Fabian and Yonghong Zhou and Karli McSweeney and Lien Le and Fiona Amante and Ashraful Haque and Amanda Stanley and Tonia Woodberry and Ervi Salwati and Donald Granger and Maurine Hobbs and Ric Price and Weinberg, {J Brice} and Grant Montgomery and Nicholas Anstey and Christian Engwerda",
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    Randall, L, Kenangalem, E, Lampah, D, Tijitra, E, Mwaikambo, E, Handojo, T, Piera, K, Zhao, ZZ, de Labastida Rivera, F, Zhou, Y, McSweeney, K, Le, L, Amante, F, Haque, A, Stanley, A, Woodberry, T, Salwati, E, Granger, D, Hobbs, M, Price, R, Weinberg, JB, Montgomery, G, Anstey, N & Engwerda, C 2010, 'A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults', Malaria Journal, vol. 9, 302, pp. 1-9. https://doi.org/10.1186/1475-2875-9-302

    A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults. / Randall, Louise; Kenangalem, Enny; Lampah, Daniel; Tijitra, Emiliana; Mwaikambo, Esther; Handojo, Tjandra; Piera, Kim; Zhao, Zhen Zhen; de Labastida Rivera, Fabian; Zhou, Yonghong; McSweeney, Karli; Le, Lien; Amante, Fiona; Haque, Ashraful; Stanley, Amanda; Woodberry, Tonia; Salwati, Ervi; Granger, Donald; Hobbs, Maurine; Price, Ric; Weinberg, J Brice; Montgomery, Grant; Anstey, Nicholas; Engwerda, Christian.

    In: Malaria Journal, Vol. 9, 302, 29.10.2010, p. 1-9.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults

    AU - Randall, Louise

    AU - Kenangalem, Enny

    AU - Lampah, Daniel

    AU - Tijitra, Emiliana

    AU - Mwaikambo, Esther

    AU - Handojo, Tjandra

    AU - Piera, Kim

    AU - Zhao, Zhen Zhen

    AU - de Labastida Rivera, Fabian

    AU - Zhou, Yonghong

    AU - McSweeney, Karli

    AU - Le, Lien

    AU - Amante, Fiona

    AU - Haque, Ashraful

    AU - Stanley, Amanda

    AU - Woodberry, Tonia

    AU - Salwati, Ervi

    AU - Granger, Donald

    AU - Hobbs, Maurine

    AU - Price, Ric

    AU - Weinberg, J Brice

    AU - Montgomery, Grant

    AU - Anstey, Nicholas

    AU - Engwerda, Christian

    PY - 2010/10/29

    Y1 - 2010/10/29

    N2 - BackgroundSevere malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.MethodsAn extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.ResultsNo associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.ConclusionsThese results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

    AB - BackgroundSevere malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.MethodsAn extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.ResultsNo associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.ConclusionsThese results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

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    KW - controlled study

    KW - disease severity

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    KW - gene locus

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    KW - genotype

    KW - haplotype

    KW - human

    KW - Indonesia

    KW - LTA gene

    KW - LTB gene

    KW - malaria falciparum

    KW - nonhuman

    KW - Plasmodium falciparum

    KW - preschool child

    KW - school child

    KW - single nucleotide polymorphism

    KW - tnf gene

    KW - genetic predisposition

    KW - genetics

    KW - immunology

    KW - Papua New Guinea

    KW - pathology

    KW - Adult

    KW - Child

    KW - Child, Preschool

    KW - Genetic Predisposition to Disease

    KW - Humans

    KW - Lymphotoxin-alpha

    KW - Lymphotoxin-beta

    KW - Malaria, Falciparum

    KW - Polymorphism, Single Nucleotide

    KW - Tumor Necrosis Factor-alpha

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