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Title: TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.
Author(s): Ferwerda, E.B. ; McCall, M.B.B. ; Alonso, S.; Giamarellos, E.J. ; Mouktaroudi, M. ; Izagirre, N.; Syafruddin, D.; Kibiki, G.S. ; Cristea, T.; Hijmans, A.G.M. ; Hamann, L.; Israel, S.; ElGhazali, G.; Troye-Blomberg, M.; Kumpf, O.; Maiga, B.; Dolo, A.; Doumbo, O.; Hermsen, C.C. ; Stalenhoef, A.F.H. ; Crevel, R. van ; Brunner, H.G. ; Oh, D.Y.; Schumann, R.R.; Rua, C. de la; Sauerwein, R.W. ; Kullberg, B.J. ; Ven, A.J.A.M. van der ; Meer, J.W.M. van der ; Netea, M.G.
Publication year: 2007
Source: Proceedings of the National Academy of Sciences USA, vol. 104, iss. 42, (2007), pp. 16645-16650
ISSN: 0027-8424
DOI: https://doi.org/10.1073/pnas.0704828104
Publication type: Article / Letter to editor

Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/52276   https://hdl.handle.net/2066/52276

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Subject: IGMD 3: Genomic disorders and inherited multi-system disorders
IGMD 5: Health aging / healthy living
N4i 1: Pathogenesis and modulation of inflammation
N4i 2: Invasive mycoses and compromised host
N4i 3: Poverty-related infectious diseases
N4i 4: Auto-immunity, transplantation and immunotherapy
NCEBP 13: Infectious diseases and international health
NCEBP 14: Cardiovascular diseases
NCMLS 1: Immunity, infection and tissue repair
NCMLS 1: Infection and autoimmunity
NCMLS 6: Genetics and epigenetic pathways of disease
UMCN 2.2: Vascular medicine and diabetes
UMCN 4.1: Microbial pathogenesis and host defense
UMCN 5.1: Genetic defects of metabolism
Organization: Internal Medicine
Medical Microbiology
Human Genetics
Journal title:
Proceedings of the National Academy of Sciences USA
Volume: vol. 104
Issue: iss. 42
Page start: p. 16645
Page end: p. 16650
Abstract:
Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.

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