Title of project

Klinefelter syndrome and male hypogonadism – a human disease model for investigating genotype-phenotype relations associable with cardiometabolic risk and testosterone replacement therapy

Abstract

Klinefelter syndrome (KS; 47,XXY) leads to male hypogonadism and is associated with increased mortality and high rates of cardiometabolic diseases. How the presence of an extra X chromosome conjures the distinct clinical phenotype of KS is unknown, but emerging evidence suggest that KS exerts an influence on gene expression throughout the entirety of the genome.

We hold data from one of the largest clinical cohorts of men with KS, and want to apply KS as a congenital model for investigating genotype-phenotype relations associable to hypogonadism and cardiometabolic risk. We hypothesize that KS is associated with a unique genomic landscape and that epigenetic and transcriptomic alterations among men with KS relate to the clinical phenotype, e.g. hypogonadism, obesity and high cardiometabolic risk. Significantly, KS is associated with low-grade inflammation and very low fibrinolytic capacity likely contributing to the 4-6 fold increased susceptibility to venous thrombosis in KS. Our aim is to meticulously evaluate features of fibrin clot formation and immunothrombosis in KS and the relation to the genetic profile.

Men with KS undergo testosterone replacement therapy (TRT). We further hypothesize that TRT is capable of ameliorating the undesirable cardiometabolic profile in KS, and exert an influence on the genomic landscape of the syndrome.

Finally, we want to present the most comprehensive epidemiological description of treatment effects on incidence and clinical control of metabolic and inflammatory disorders in KS. We have at our disposal, the largest registry based cohort of men with KS, with access to an extensive array of health-related data, including prescriptions and laboratory findings. The project applies a wide range of novel methodologies and relies on collaborations between several national and international experts.

The project will provide new multi-level information regarding disease mechanisms in KS and will help identify future targets for improving treatment of KS. Applying KS as cardiometabolic disease model could allow findings from the studies to translate to other populations with hypogonadism or high cardiometabolic risk.