Zusammenfassung
Die homozygote Sichelzellerkrankung (HbSS Krankheit) ist paradigmatisch für den komplexen
Einfluss von genetisch modifizierenden Faktoren auf das klinische Bild einer monogenen
Krankheit. Insbesondere beeinflusst die genetisch bedingte Variabilität der HbF-Konzentration
die klinische Ausprägung der HbSS-Krankheit erheblich. Die erfolgreiche, mit einer
verminderten Morbidität einhergehende medikamentöse Erhöhung der HbF-Konzentration
zeigt, dass die Kenntnis der modulierenden genetischen Faktoren neue Möglichkeiten
der therapeutischen Intervention eröffnen kann. In geringerem Maße lässt sich eine
Assoziation von Schwere der Erkrankung und koinzident auftretender α-Thalassämie erkennen.
Beide Faktoren, HbF und α-Thalassämie, können alleine die Vielfalt und Variabilität
des klinischen Spektrums der HbSS-Krankheit nicht ausreichend erklären. Mit Methoden
der Genomforschung wurden relevante Genloki identifiziert, die möglicherweise zur
Abschätzung der Wahrscheinlichkeit des Auftretens schwerer Komplikationen der Sichelzellerkrankung
wie etwa von Schlaganfällen genutzt werden können. Die subtile Analyse der genetisch
modifizierenden Einflussfaktoren wird das Management von Patienten mit Sichelzellkrankheit
nach dem Vorliegen von Ergebnissen prospektiver Studien somit voraussichtlich wesentlich
beeinflussen.
Abstract
Homozygous sickle cell (HbSS) disease is paradigmatic for the complex influence of
genetic modifiers of a monogenic disease. The genetically determined variability of
HbF concentration has a strong impact on the clinical phenotype. The pharmacologically
induced increase of HbF leads to a reduced morbidity which demonstrates that the knowledge
of genetic modifiers enables the development of new therapeutic strategies. The presence
of α-thalassemia also ameliorates the disease phenotype albeit not to the same extent
as HbF does. Both factors, HbF and α-thalassemia are insufficient to explain the clinical
variability of HbSS disease. The introduction of genome analysis has now provided
the tools to identify relevant gene loci that will likely be helpful in estimating
the probability of severe complications such as the occurrence of stroke. Following
the validation in prospective studies, the subtle analysis of genetic modifiers will
therefore influence the management of patients with sickle cell disease.
Schlüsselwörter
Sichelzellerkrankung - genetische Modulation - fetales Hämoglobin (HbF) - α-Thalassämie
- single nucleotide polymorphism (SNP)
Key words
sickle cell disease - genetic modulation - fetal haemoglobin (HbF) - α-thalassemia
- single nucleotide polymorphism (SNP)
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Kathrin Hartmann
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und Immunologie
Im Neuenheimer Feld 153
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Email: Kathrin.Hartmann@med.uni-heidelberg.de
