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.
|
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
|
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.
|