Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Tropical Medicine Section
Human genetic variants influencing
resistance to malaria
Zusammenfassung
Um neue Methoden der Prävention und Bekämpfung
der Malaria zu entwickeln, wird untersucht,
wie Menschen natürlicherweise vor Malaria
geschützt sein können. Aufgrund ihrer hohen Kindersterblichkeit
hat Malaria die Selektion zahlreicher
genetischer Anlagen des Menschen bewirkt, die
eine gewisse Resistenz oder Protektion vor Malaria
vermitteln. Die Aufklärung dieser Faktoren könnte
auf Stoffwechselwege hinweisen, die vor Malaria-
Parasitämie und klinischer Erkrankung schützen.
In einem Endemiegebiet der Malaria in Ghana
wurden 120 Familien ausgewählt, die keine der
möglicherweise schützenden Erythrozyten-Anomalien
zeigen. Aus diesen Familien wurden über 450
Geschwisterkinder über 8 Monate wöchentlich auf
Malariaparasiten und klinische Zeichen einer Malaria
untersucht. Derzeit wird eine Kopplungsanalyse
durchgeführt, um neue genetische Resistenzfaktoren
zu suchen. Darüber hinaus wurden über 2000 Fälle
von komplizierter Malaria und entsprechende
Kontrollpersonen untersucht und in eine Studie
aufgenommen, die das Ziel hat, genetische Faktoren
zu identifizieren, die vor komplizierter Malaria
schützen. In Anbetracht der enormen Bedeutung
der Medikamentenresistenz von Malariaparasiten
und ihres möglichen Einflusses auf das klinische Bild
der Malaria wurde ein neuer massenspektrometrischer
Test entwickelt, der die Sensitivität der
Identifizierung medikamentenresistenter Isolate bei
multiplen Infektionen deutlich verbessert.
Summary
Naturally occurring mechanisms of resistance and
protection are being studied in order to develop novel
means of prevention and control. It is generally accepted
that malaria, particulary becaue of its high childhood
mortality, has selected for many, as yet unknown
human genetic traits. These might indicate metabolic
pathways which protect against parasitaemia and clinical
disease. Thus, 120 families were selected not to carry
any of the possibly protective red-cell disorders. Of
those, more than 450 siblings were closely monitored
for parasitaemia and mild malaria over a period of 8
months. Presently, a linkage analysis is being performed
to search for novel genetic resistance factors.
In addition, more than 2000 cases of severe and complicated
malaria have been examined and included in a
study aiming at genetic factors which protect from severe
disease. With regard to the enormous importance
of drug-resistant malaria and its possible influence on
clinical disease presentation, a new mass-spectrometry
assay was developed which substantially increases the
80
sensitivity of identifying drug-resistant isolates in
multiple infections.
Introduction
Drawbacks in vaccine development and problems of
drug resistance have stressed the demand for research
on fundamental issues in plasmodium biology and
malaria pathology. One approach to identify possible
routes of prevention and control is to unravel naturally
occurring mechanisms of resistance and protection.
Protection against severe malaria has clearly been
shown to be mediated by certain red-cell disorders and
by genetic variants of several immune response and
effector molecules. It is generally accepted that malaria
has in exposed populations selected for many more
human genetic traits.
Project Description and Results
Phenotyping for parasitaemia and mild malaria
In holoendemic malaria areas such as our study sites in
the vicinity of Kumasi, Ghana, all residents are exposed
to malaria transmission. Therefore, virtually all children
for various periods of time and to various degrees carry
malaria parasites in their blood while they develop
partial immunity. Occasionally and, again with considerable
inter-individual variability, these parasitaemias
cause mild clinical disease and, rarely and in 1-2% of
children only, severe and complicated malaria (see
below). Since parasitaemias and mild clinical malaria
episodes affect virtually all children and thus all siblings
of a given family, they are accessible to a genetic linkage
study using a quantitative-trait analysis. For this
approach, 2600 parental pairs who have more than 3
children aged 0.5 to 11 years were genetically examined
not to carry any of the known or assumed red-cell
malaria resistance factors of haemoglobin (Hb)S and C,
a-thalassaemia and glucose-6-phosphate dehydrogenase
deficiency A-. 120 families were identified, and the
children (450 forming 650 sib-pairs) were thoroughly
phenotyped for malaria parasitaemias and mild disease
over an entire rainy season by weekly visits including interrogations
and malaria smears and biweekly haematocrits.
The phenotyping procedure required more than
14,000 home visits, whereby the compliance was >99%.
Phenotype data are presently being evaluated, first
results confirm the current concept of the acquisition of
partial malaria immunity during childhood (Fig.1), at the
same time showing the quality of the phenotype data.
Interestingly, 1-2% of children never had parasitaemias.
At present, the children are being genotyped at 10,000
genome-wide single-nucleotide polymorphisms applying
microarrays at the DNA-typing centre of the National
Genome Research Network (NGFN).