Discovery of coding genetic variants influencing diabetes-related serum biomarkers and their impact on risk of type 2 diabetes.

ABSTRACT

CONTEXT Type 2 diabetes (T2D) prevalence is spiraling globally, and knowledge of its pathophysiological signatures is crucial for a better understanding and treatment of the disease. OBJECTIVE: We aimed to discover underlying coding genetic variants influencing fasting serum levels of nine biomarkers associated with T2D adiponectin, C-reactive protein, ferritin, heat shock 70-kDa protein 1B, IGF binding protein 1 and IGF binding protein 2, IL-18, IL-2 receptor-α, and leptin. DESIGN AND PARTICIPANTS: A population-based sample of 6215 adult Danes was genotyped for 16 340 coding single-nucleotide polymorphisms and were tested for association with each biomarker. Identified loci were tested for association with T2D through a large-scale meta-analysis involving up to 17 024 T2D cases and up to 64 186 controls. RESULTS: We discovered 11 associations between single-nucleotide polymorphisms and five distinct biomarkers at a study-wide P < 3.4 × 10(-7). Nine associations were novel IL18 BIRC6, RAD17, MARVELD2; ferritin F5; IGF binding protein 1 SERPING1, KLKB, GCKR, CELSR2, and heat shock 70-kDa protein 1B CFH. Three of the identified loci (CELSR2, HNF1A, and GCKR) were significantly associated with T2D, of which the association with the CELSR2 locus has not been shown previously. CONCLUSION: The identified loci influence processes related to insulin signaling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.