Study of the glycated hemoglobin in type 1 diabetes patients ; Étude de l’hémoglobine glyquée chez des patients diabétiques de type 1

Despite technological advances over the past 20 years, the control of blood glucose level is still a major challenge for children with type 1 diabetes (T1D), with some patients never achieving correct glycemic control (estimated by glycated hemoglobin level, HbA1c), leading to severe long-term complications. To date, there is no joint study of the clinical, epidemiological and genetic factors influencing HbA1c level. The objective of my PhD was therefore to study all these factors and is organized in three parts. First we studied the statistical properties of a genetic association test, the General Regression Model (GRM), for a quantitative trait. Indeed, large-scale genetic association studies of quantitative traits often use linear regression (LR) models assuming a dose effect of the risk allele (additive model, LR_ADD), resulting in a loss of power in case of deviation from the additivity. The GRM does not make any assumptions about the mode of transmission and formally test it. We compared the statistical properties of GRM to LR tests for a large number of genetic models by a simulation study, showing that GRM may be as powerful as LR_ADD under an additive model, and can be more powerful when there is a deviation from the additivity. The transmission model test concluded to the simulated model in most cases. In a second step, we systematically reviewed the literature on factors influencing HbA1c level in young T1D patients between 2010 and July 2016. For non-genetic factors, 1974 articles were identified and then 78 selected. Most of these articles studied the effect of a particular factor on HbA1c levels. The main factors influencing HbA1c levels are pubertal status, socio-economic status, ethnicity, duration of T1D, adherence and treatment. For genetic factors, 277 articles were identified and 14 were selected. Most of these studies have focused on candidate genes in small samples. This work highlights the importance to jointly study factors influencing HbA1c. Finally, I participated to the GENDIR project, ...