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

Tarun Veer Singh Ahluwalia, Kristine Højgaard Allin, Camilla Helene Sandholt, Thomas Hempel Sparsø, Marit Eika Jørgensen, Michael Rowe, Cramer Christensen, Ivan Brandslund, Torsten Lauritzen, Allan Linneberg, Lise Lotte Nystrup Husemoen, Torben Jørgensen, Torben Hansen, Niels Grarup, Oluf Borbye Pedersen

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume100
Issue number4
Pages (from-to)E664-71
ISSN0021-972X
DOIs
Publication statusPublished - 19 Jan 2015

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