TY - JOUR
T1 - Discovery of coding genetic variants influencing diabetes-related serum biomarkers and their impact on risk of type 2 diabetes
AU - Ahluwalia, Tarun Veer Singh
AU - Allin, Kristine Højgaard
AU - Helene Sandholt, Camilla
AU - Hempel Sparsø, Thomas
AU - Eika Jørgensen, Marit
AU - Rowe, Michael
AU - Christensen, Cramer
AU - Brandslund, Ivan
AU - Lauritzen, Torsten
AU - Linneberg, Allan
AU - Husemoen, Lise Lotte Nystrup
AU - Jørgensen, Torben
AU - Hansen, Torben
AU - Grarup, Niels
AU - Pedersen, Oluf Borbye
PY - 2015/1/19
Y1 - 2015/1/19
N2 - Context: Type 2 diabetes (T2D) prevalence is spiralling 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 (CRP), ferritin, heat-shock 70kDa protein 1B (HSPA1B), insulin-like growth factor binding protein 1 (IGFBP1) and 2 (IGFBP2), interleukin 18 (IL18), interleukin 2 receptor alpha (IL2RA), and leptin. Design and Participants: A population-based sample of 6,215 adult Danes was genotyped for 16,340 coding single-nucleotide polymorphisms (SNPs) and 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 SNPs and five distinct biomarkers at a study-wide P < 3.4 × 10(-7). Nine associations were novel: IL18: BIRC6, RAD17, MARVELD2; ferritin: F5; IGFBP1: SERPING1, KLKB, GCKR, CELSR2 and HSPA1B: 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 signalling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.
AB - Context: Type 2 diabetes (T2D) prevalence is spiralling 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 (CRP), ferritin, heat-shock 70kDa protein 1B (HSPA1B), insulin-like growth factor binding protein 1 (IGFBP1) and 2 (IGFBP2), interleukin 18 (IL18), interleukin 2 receptor alpha (IL2RA), and leptin. Design and Participants: A population-based sample of 6,215 adult Danes was genotyped for 16,340 coding single-nucleotide polymorphisms (SNPs) and 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 SNPs and five distinct biomarkers at a study-wide P < 3.4 × 10(-7). Nine associations were novel: IL18: BIRC6, RAD17, MARVELD2; ferritin: F5; IGFBP1: SERPING1, KLKB, GCKR, CELSR2 and HSPA1B: 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 signalling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.
U2 - 10.1210/jc.2014-3677
DO - 10.1210/jc.2014-3677
M3 - Journal article
C2 - 25599387
SN - 0021-972X
VL - 100
SP - E664-71
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 4
ER -