Impact of the GH-IGF-I axis in adults - pharmacogenetic and genetic association studies

Abstract

Growth hormone (GH) is a polypeptide hormone which is secreted from the anterior pituitary in a pulsatile pattern. GH is best known by its strong effects on longitudinal growth in children, but the importance of GH is maintained also in adulthood due to the powerful effects on cellular differentiation and fuel homeostasis. GH deficient (GHD) adults often present with abdominal obesity, insulin resistance and an almost doubled risk for cardiovascular mortality. These problems are to a varying extent reversed during GH replacement therapy (GHRT). Variability in treatment response is large and probably at least partly mediated by genetic variation. The effects of GH are mediated by the GH receptor (GHR), a transmembrane glycoprotein expressed on most human cell types. In humans, there are two isoforms of the GHR which differ in regards to retention (fl-GHR) or exclusion (d3-GHR) of exon 3. The two isoforms are simply two different alleles of a common GHR polymorphism (the GHR d3/fl polymorphism), which has been suggested to influence GH sensitivity.

This thesis is based on four studies, with the common, overall, aim to test the hypothesis that polymorphisms in genes within the GH-IGF-I axis influence body composition, metabolism and serum IGF-I concentrations.

In an initial study we found that the GHR d3/fl polymorphism was not associated with the 1 year changes in IGF-I concentrations and body composition in response to GHRT. During this study, which was fairly small, we realized the need for a different genotyping method for analyses of the GHR d3/fl polymorphism in larger cohorts. Therefore, in the subsequent study, we evaluated the use of tagSNP rs6873545 as a marker for the GHR d3/fl polymorphism, and showed that it does indeed perfectly tag the different GHR d3/fl alleles. In the next study, we investigated the impact of the GHR SNP rs6873545 and five other polymorphisms in genes within the GH-IGF-I axis on the early and the long-term IGF-I responses to GHRT in a large cohort of GHD adults. In this study we found that the GHR SNP rs6873545 and the PIK3CB SNP rs361072 were associated with the early, but not the long-term, IGF-I response. In the last study, we analysed the tagSNP rs6873545 in a study representative of the general Swedish population and found that homozygosity for the d3-GHR was associated with an adverse anthropometric and metabolic profile.

In conclusion, the results of this thesis suggests that 1) the GHR d3/fl polymorphism is indeed of functional importance, and influences both the response to GHRT in GHD adults as well as body composition and metabolism in the general Swedish population, and 2) other SNPs in genes within the GH-IGF-I axis may be of an equal importance in terms of the response to GHRT in GHD adults.