Genetic and immunological risk factors of gestational diabetes mellitus

Abstract: Gestational diabetes mellitus (GDM) is a heterogeneous disorder that is defined as carbohydrate intolerance with onset or first recognition during pregnancy. Impaired beta-cell function and insulin resistance are the hallmarks of GDM. The overall aim of this thesis was to study the genetic and immunological risk factors that increase susceptibility to GDM. First, we investigated whether autoimmunity and genetic variants affecting insulin secretion or action, or both, contribute to the development of GDM. We found that GDM was associated with the presence of glutamic acid decarboxylase-65 antibodies (GAD65Ab) in Arabian and Scandinavian women. In addition, Scandinavian women with GDM were found to share some genetic features such as HLA DQB1 risk genotypes (odds ratio [OR] 1.36, [95% CI 1.03?1.79], p=0.03) with type 1 diabetes. Furthermore, Arabian women with GDM were more insulin resistant than Scandinavian women with GDM and with the same BMI. We also investigated whether GDM has a similar genetic predisposition as type 2 diabetes by studying common genetic polymorphisms that have previously been associated with type 2 diabetes. Among 5 studied polymorphisms, we found that the E23K polymorphism of the potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene was associated with a modestly increased risk (1.17, [1.02?1.35], p=0.027) of GDM. This is compatible with its effect on insulin secretion and the crucial role of impaired beta-cell function in the pathogenesis of GDM. Additionally, we studied whether common variants in MODY [Glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), and HNF4A] genes also increase the risk of GDM. We found that the A-allele of the ?30G>A polymorphism in the beta-cell-specific promoter of the GCK increases the risk of GDM with a modest OR of 1.28 ([1.06 ?1.53], p=0.008). Moreover, the HNF1A I27L polymorphism was also associated with an increased risk of GDM (1.16 [1.001?1.34], p=0.048). All these variants are supposed to influence beta-cell function. Finally, we tested whether common genetic variants that have been associated with the metabolic syndrome or its components would also confer risk for GDM. We found that the T-allele of the +276G>T polymorphism of the adiponectin (APM1) gene, which has previously been associated with insulin resistance, increases the risk of GDM with an OR of 1.17 ([1.01?1.36], p=0.039). We conclude that common variants in several type 1 and type 2 diabetes candidate genes in addition to immunological factors increase susceptibility to heterogeneous GDM.