Genetisches Risiko für Adipositas bei Kindern und Jugendlichen

ZUSAMMENFASSUNG

Adipositas ist eine komplexe Erkrankung, die sowohl genetischen wie auch nicht-genetischen Ursachen zugrunde liegt. Betrachtet man den BMI als einfaches Maß für die Fettleibigkeit, liegt die geschätzte Heritabilität sowohl bei Erwachsenen wie auch bei Kindern bei 0,7. Das Verständnis über die Rolle genetischer Faktoren bei polygener Adipositas bleibt eine der größten Herausforderungen. Obwohl kandidatengenbasierte sowie genomweite Kopplungsstudien mehrere Jahrzehnte dominierten, ermöglichen heute neue Technologien im Hochdurchsatz das Genotypisieren von Millionen genetischer Varianten, wodurch der Weg für genomweite Assoziationsstudien (GWAS) geebnet wurde. Diese stellen nach wie vor das effizienteste Werkzeug dar, um neue genetische Marker mit Assoziation zur Adipositas zu entdecken. Bis heute wurden so hunderte Polymorphismen im Zusammenhang mit der Fettleibigkeit identifiziert, darunter auch Varianten in Genen wie FTO, TMEM18 und MC4R. Obwohl viele dieser Gene auch mit der Fettleibigkeit im Kindesalter in Verbindung zu stehen scheinen, haben umgekehrt auch Studien in Kohorten von Kindern und Jugendlichen zur initialen Entdeckung weiterer mit Adipositas assoziierter Gene (z. B. OLFM4 und HOXB5) geführt. Auch wenn die komplette Entschlüsselung der Adipositas-Genetik nach wie vor eine große Herausforderung bleibt, könnte ein besseres Verständnis über das genetische Risiko in die klinische Praxis übertragen werden. So kann man basierend auf der Vielzahl bekannter genetischer Varianten sogenannte Polygenic Risk Scores nutzen, um Kinder und Jugendliche mit einem erhöhten Risiko für die Entwicklung einer Adipositas zu identifizieren, und so möglichst frühzeitig deren Manifestierung und damit verbunden Konsequenzen entgegenzuwirken.

ABSTRACT

Obesity is a complex disease resulting from an interplay of genetic and nongenetic factors. Although heritability estimates for body mass index (BMI) in childhood and adults account for up to 70 %, better understanding of the genetic factors in polygenic obesity remains a major challenge. Whereas genome-wide linkage analyses as well as candidate gene strategies have been the dominating research efforts over several decades, current advances in DNA technologies allowing genotyping of millions of genetic variants have paved new avenues for research approaches like genome-wide association studies (GWAS). This resulted in uncovering of hundreds of genetic variants associated with obesity, which map within genes such as FTO, TMEM18, MC4R. Majority of these genes found in cohorts of adults seem to play a role in childhood obesity as well. Nevertheless, also studies in children and adolescents contributed to initial identification of additional obesity susceptibility genes (e. g. OLFM4 and HOXB5). Explaining the heritability of obesity is immensely important since better knowledge of the genetics could have a large impact in the clinical world as well. In this context, polygenic risk scores based on contribution of numerous obesity susceptibility variants might help to identify children at high risk of obesity and so, allow early intervention against the disease as well as its metabolic consequences.

Schlüsselwörter

Adipositas - genetisches Risiko - Polygenic Risk Score

Keywords

Genetic risk - obesity - childhood - polygenic risk score - genome-wide association study

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