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 Price; J Brice Weinberg; Grant Montgomery; Nicholas Anstey; Christian Engwerda

doi: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

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 language	English
Article number	302
Pages (from-to)	1-9
Number of pages	9
Journal	Malaria Journal
Volume	9
DOIs	https://doi.org/10.1186/1475-2875-9-302
Publication status	Published - 29 Oct 2010

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Randall, L., Kenangalem, E., Lampah, D., Tijitra, E., Mwaikambo, E., Handojo, T., Piera, K., Zhao, Z. Z., de Labastida Rivera, F., Zhou, Y., McSweeney, K., Le, L., Amante, F., Haque, A., Stanley, A., Woodberry, T., Salwati, E., Granger, D., Hobbs, M., ... 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

@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",

year = "2010",

month = oct,

day = "29",

doi = "10.1186/1475-2875-9-302",

language = "English",

volume = "9",

pages = "1--9",

journal = "Malaria Journal",

issn = "1475-2875",

publisher = "BioMed Central",

}

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

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.

KW - lymphotoxin

KW - lymphotoxin beta

KW - tumor necrosis factor

KW - LTB protein, human

KW - TNF protein, human

KW - tumor necrosis factor alpha

KW - adult

KW - article

KW - brain malaria

KW - child

KW - chromosome 6

KW - controlled study

KW - disease severity

KW - gene

KW - gene linkage disequilibrium

KW - gene locus

KW - gene sequence

KW - genetic susceptibility

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

UR - http://www.scopus.com/inward/record.url?scp=77958601047&partnerID=8YFLogxK

U2 - 10.1186/1475-2875-9-302

DO - 10.1186/1475-2875-9-302

M3 - Article

VL - 9

SP - 1

EP - 9

JO - Malaria Journal

JF - Malaria Journal

SN - 1475-2875

M1 - 302

ER -

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

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