Genome-wide association study indicates two novel resistance loci for severe malaria.
Malaria causes approximately one million fatalities per year, mostly among African children. Although highlighted by the strong protective effect of the sickle-cell trait, the full impact of human genetics on resistance to the disease remains largely unexplored. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.
Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. timmann@bnitm.de
Christian
C
Timmann
Thorsten
T
Thye
Maren
M
Vens
Jennifer
J
Evans
Jürgen
J
May
Christa
C
Ehmen
Jürgen
J
Sievertsen
Birgit
B
Muntau
Gerd
G
Ruge
Wibke
W
Loag
Daniel
D
Ansong
Sampson
S
Antwi
Emanuel
E
Asafo-Adjei
Samuel Blay
SB
Nguah
Kingsley Osei
KO
Kwakye
Alex Osei Yaw
AO
Akoto
Justice
J
Sylverken
Michael
M
Brendel
Kathrin
K
Schuldt
Christina
C
Loley
Andre
A
Franke
Christian G
CG
Meyer
Tsiri
T
Agbenyega
Andreas
A
Ziegler
Rolf D
RD
Horstmann
D000017:ABO Blood-Group System; D000755:Anemia, Sickle Cell; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D060467:Disease Resistance / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D005869:Ghana; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics* / Q000469:parasitology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D000017:ABO Blood-Group System; C548163:MARVELD3 protein, human; D008565:Membrane Proteins; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases