Clinical genetics of Type 1 Diabetes Genetic correlates of early growth and disease progression

Kharagjitsing, A.V. (2011)

Doctoral Thesis

Several years ago we embarked on a journey, aiming to identify the molecular mechanisms of candidate risk genes for type 1 diabetes (T1D), focusing on their role in disease pathogenesis. In this context, we studied phenomena of T1D with clinical relevance in great detail and aimed to find genetic correlates of these. This thesis can be considered the clinical chapter of this journey providing validation and extension of several clinically relevant gene polymorphisms with functional consequences in relation to growth (INS-VNTR, IGF1, disease progression and remission (IFN-_, IL-10,), islet autoimmunity (INS-VNTR), and environment (Lewis). We found: Increased early growth, rather than birth weight, to be a risk factor for T1D; Accelerated growth preceding T1D is limited to early life i.e. to the 1st year of life ; Early in life and in contrast to the INS-VNTR, an IGF-1 variant is associated with T1D via accelerated growth ; Remission or disease progression is at least partially immune-mediated ; IFN-_ levels, along with their corresponding genotypes, could be valuable in predicting (partial) clinical remission at clinical onset of diabetes ; T1D disease mechanisms appear to overrule genetic influences in disease progression.

• VNTR
• IGF-I
• Genetic association
• Early growth
• Clinical remission
• Auto immune type 1 diabetes

• All authors: Kharagjitsing, A.V.
• Supervisor: Roep, B.O.; Bruining, G.J.
• Co-supervisor: Koeleman, B.P.C.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2011-11-30
• ISBN (print): 9789461911049
• Sponsorship: MSD Nederland Pharma ; Eli Lilly Nederland ; Novartis Pharma ; Novo Nordisk ; Ipsen Farmaceutica