Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

Anna Jonsson,Oluf Pedersen,Niels Grarup,Torben Hansen,Elisabeth R Mathiesen,Jens Juul Holst,Daniel R Witte,Kristine Færch,Marit E Jørgensen,Tine D Clausen,Louise Kelstrup,Signe S Torekov,Peter Damm,Sara E Stinson

doi:10.1186/s12920-020-00841-7

Abstract

BackgroundIn order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels.MethodsPlasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis.ResultsA known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10–4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta − 0.210, SE 0.037, P = 1.9 × 10–8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10–5).ConclusionsA type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.

Highlights

In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT)
Known type 2 diabetes associated variant associates with increased 30 min glucagon levels When analyzing the variants previously reported to associate with type 2 diabetes in the paper by Mahajan et al [15], the variant in the EYA transcriptional coactivator and phosphatase 2 (EYA2) locus was associated with higher 30 min plasma glucagon levels during the OGTT, after correction for multiple testing
Nominal association of previously reported glucagon associated variant We identified a nominal association for the variant rs28929474 on chromosome 14 in SERPINA1, reported by Almgren et al [4] to be associated with increased fasting glucagon levels

Summary

Introduction

In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). We performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Glucagon is a key regulator of hepatic glucose production and is intimately linked to type 2 diabetes pathophysiology. The most comprehensive genome-wide association study (GWAS) for glucagon so far was reported by Almgren et al [4] in 2017. They performed a meta-analysis on circulating levels of glucagon measured at two time points, 0 and 120 min, during an OGTT including 3344 Swedish individuals from Malmö Diet and Cancer study (MDC) and 4905 Finnish individuals from the Prevalence, Prediction and Prevention of diabetes Botnia study (PPPBotnia). Six suggestively associated loci to glucagon levels were reported, four for fasting levels of glucagon and two for 2 h glucagon levels [4]

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Conclusion