02234nas a2200385   4500000000100000008004100001260001700042653002500059653003100084653001900115653002000134653003800154653002200192653001300214653001900227653002000246653001100266653001400277653003300291653001200324653002200336653003700358653001200395653003200407653001100439653002700450653003200477100001500509700001800524245010400542300001000646490000800656520117000664022001401834       1999                            d  c1999 Jul-Aug10aCase-Control Studies10aGene Expression Regulation10aGene Frequency10aGenetic Linkage10aGenetic Predisposition to Disease10aGenetic Variation10agenotype10aHIV Infections10aHLA-DR3 Antigen10aHumans10aInfection10aLeishmaniasis, Mucocutaneous10aleprosy10aLymphotoxin-alpha10aMajor Histocompatibility Complex10aMalaria10aPostoperative Complications10aSepsis10aTranscription, Genetic10aTumor Necrosis Factor-alpha1 aKnight J C1 aKwiatkowski D00aInherited variability of tumor necrosis factor production and susceptibility to infectious disease.  a290-80 v1113 a<p>Tumor necrosis factor (TNF) is a critical mediator of host defense against infection but may cause severe pathology when produced in excess. Individuals vary in the amount of TNF produced when their peripheral blood mononuclear cells are stimulated in vitro, and family studies indicate that much of this variability is genetically determined. Since the TNF response to infection is partly regulated at the transcriptional level, TNF promoter polymorphisms have been the subject of intense interest as potential determinants of disease susceptibility. A single nucleotide polymorphism at nucleotide -308 relative to the transcriptional start site has been associated with susceptibility to severe malaria, leishmaniasis, scarring trachoma, and lepromatous leprosy. Some experimental data indicate that this polymorphism acts to upregulate TNF transcription, but this remains controversial. Detailed analysis of multiple genetic markers at this locus and more sophisticated investigations of TNF transcriptional regulation, in different cell types and with a wide range of stimuli, are required to understand the molecular basis of these disease associations.</p>  a1081-650X