Genetic biomarker linked to subcutaneous growth hormone dose-response

The interindividual variability of response to subcutaneously applied protein-based drugs remains poorly understood. However, defining genetic markers that can be associated with biological effects of such drugs may improve the understanding of individual variability of response and even drug resistance.

A team of German scientists has shown for the first time that a genetic biomarker may explain individual differences in the required dosage of subcutaneously injected recombinant human growth hormone (hGH). The team, led by Dr Peter Kann of Philipps-University Marburg, Germany, found significant association between the collagen type I alpha 1 specific protein 1 polymorphism (COLIA1) Sp1 polymorphism and the dose of subcutaneously injected recombinant human growth hormone (hGH) required in GH-deficient adults. Their findings are published in the August issue of Pharmacogenomics.

The study looked at the guanine (G)-to-thymidine (T) polymorphism in a Sp1 binding site of the COLIA1 gene. This G/T sequence variant can easily be identified by modern molecular biology techniques. The team determined the COLIA1 Sp1 polymorphism in 122 adults with GH-deficiency of different origin who had been treated with hGH for more than 12 months. In the study, T-allele-carriers were treated with significantly lower hGH-doses compared to the GG-homozygotes, but came to an equivalent clinical outcome reflected by IGF-1 response to hGH substitution.

Commenting on the paper, Dr David Gurwitz of Tel-Aviv University and an Associate Editor of Pharmacogenomics said, "The study is the first description of a genetic factor influencing responsiveness to subcutaneously applied protein-based drugs. The authors hypothesize that the relationship they have discovered may reflect different levels or structures of subcutaneous collagen type I which in turn affect the bioavailability of the injected hormone. If they are correct (which must await further studies) their findings may extend to a large variety of injected hormones or peptides which may be similarly affected by the skin collagen levels or structure."

Commenting on the wider implications of the study, Dr Kann stated, "One very interesting aspect is that the relationship of the COLIA1 polymorphism to effect of subcutaneously administered GH might not be restricted only to GH, but may also be relevant for other drugs injected subcutaneously."

Dr Gurwitz added a note of caution in interpreting the study, "The main weakness of the study is its small size (n = 122). Pharmacogenetics studies typically require much larger patient cohorts. Confirmatory studies would be needed before conclusions, and clinical applications, can be considered."

The authors hope that this is only the first step in developing a good understanding of how genetic factors influence absorption capacity, bioavailability and/or biological effects of and resistance against subcutaneously administered protein-based drugs by modifying mechanical and/or biological properties of the subcutenaous connective tissue.

In an accompanying Guest Editorial published in the same issue, Christian Koch, Professor of Medicine and Director, Division of Endocrinology, University of Mississippi Medical Center, places this advance in context and highlights how further studies may point the way toward individualized pharmacogenomic therapy.