The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

Bidragets oversatte titel: The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals

N. Grarup, Maria Overvad, T. Sparsø, D. R. Witte, C. Pisinger, T. Jørgensen, T. Yamauchi, K. Hara, S. Maeda, T. Kadowaki, Torben Hansen, O. Pedersen

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Abstrakt

AIMS/HYPOTHESIS: A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits.

METHODS: We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT.

RESULTS: The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 × 10(-5)) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 × 10(-4)). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (β = -0.039, p = 2 × 10(-7)), insulinogenic index (β = -0.057, p = 1 × 10(-8)) and BIGTT-acute insulin release (β = -0.041, p = 9 × 10(-9)). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R (2) < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305.

CONCLUSIONS/INTERPRETATION: The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait.

OriginalsprogEngelsk
TidsskriftDiabetologia
Vol/bind54
Udgave nummer4
Sider (fra-til)789-794
ISSN0012-186X
DOI
StatusUdgivet - 2011

Bibliografisk note

Grarup, N. Overvad, M. Sparso, T. Witte, D. R. Pisinger, C. Jorgensen, T. Yamauchi, T. Hara, K. Maeda, S. Kadowaki, T. Hansen, T. Pedersen, O.

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  • Citationsformater

    Grarup, N., Overvad, M., Sparsø, T., Witte, D. R., Pisinger, C., Jørgensen, T., Yamauchi, T., Hara, K., Maeda, S., Kadowaki, T., Hansen, T., & Pedersen, O. (2011). The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals. Diabetologia, 54(4), 789-794. https://doi.org/10.1007/s00125-010-2031-2