TY - JOUR
T1 - Genome-wide association study on the early-phase insulin response to a liquid mixed meal
T2 - Results from the NEO study
AU - Li-Gao, Ruifang
AU - Carlotti, Françoise
AU - De Mutsert, Renée
AU - Van Hylckama Vlieg, Astrid
AU - De Koning, Eelco J.P.
AU - Jukema, J. Wouter
AU - Rosendaal, Frits R.
AU - Van Dijk, Ko Willems
AU - Mook-Kanamori, Dennis O.
N1 - Funding Information:
The authors thank all individuals who participated in the NEO study and all participating general practitioners for inviting eligible participants. The authors also thank the NEO study group, Pat van Beelen (Department of Clinical Epidemiology, Leiden University Medical Center) and all research nurses for data collection, Petra Noordijk (Department of Clinical Epidemiology, Leiden University Medical Center) and her team for laboratory management, and Ingeborg de Jonge (Department of Clinical Epidemiology, Leiden University Medical Center) for data management of the NEO study. The authors thank Nutricia Research, Utrecht, the Netherlands, for providing the liquid mixed meal. The NEO study is supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). D.O.M.-K. is supported by the Dutch Science Organization (ZonMW-VENI grant 916.14.023).
Funding Information:
Acknowledgments. The authors thank all individuals who participated in the NEO study and all participating general practitioners for inviting eligible participants. The authors also thank the NEO study group, Pat van Beelen (Department of Clinical Epidemiology, Leiden University Medical Center) and all research nurses for data collection, Petra Noordijk (Department of Clinical Epidemiology, Leiden University Medical Center) and her team for laboratory management, and Ingeborg de Jonge (Department of Clinical Epidemiology, Leiden University Medical Center) for data management of the NEO study. The authors thank Nutricia Research, Utrecht, the Netherlands, for providing the liquid mixed meal. Funding. The NEO study is supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). D.O.M.-K. is supported by the Dutch Science Organization (ZonMW-VENI grant 916.14.023). Duality of Interest. D.O.M.-K. is a part-time clinical research consultant for Metabolon, Inc. No other potential conflicts of interest relevant to this article were reported. Author Contributions. R.L.-G. performed the analysis and wrote and edited the manuscript. F.C. conducted the in vitro experiment and drafted and reviewed the manuscript. R.d.M. and F.R.R. contributed to study design and manuscript review. A.v.D.V., E.J.P.d.K., and J.W.J. contributed to results interpretation and manuscript review. K.W.v.D. and D.O.M.-K. contributed to study design, conceived the idea of the current study, interpreted the results, and reviewed the manuscript. R.L.-G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium meeting, Rotterdam, the Netherlands, 18–19 April 2018.
Publisher Copyright:
© 2019 by the American Diabetes Association.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 531028) and was also replicated successfully (β: 27.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.
AB - Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (β: -6.5% [minor allele frequency (MAF) 0.32, P = 3.3 × 10-8]) located in the ABO gene reached genome-wide significant level (P < 531028) and was also replicated successfully (β: 27.8% [MAF 0.32, P = 7.2 × 10-5]). The function of the ABO gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic β-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic β-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early-phase insulin secretion.
UR - http://www.scopus.com/inward/record.url?scp=85075814002&partnerID=8YFLogxK
U2 - 10.2337/db19-0378
DO - 10.2337/db19-0378
M3 - Article
C2 - 31537524
AN - SCOPUS:85075814002
SN - 0012-1797
VL - 68
SP - 2327
EP - 2336
JO - Diabetes
JF - Diabetes
IS - 12
ER -