The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals.
OBJECTIVE
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
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.
Marie Krogh Center for Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1-3, 2100 Copenhagen, Denmark. niels.grarup@sund.ku.dk
N
N
Grarup
M
M
Overvad
T
T
Sparsø
D R
DR
Witte
C
C
Pisinger
T
T
Jørgensen
T
T
Yamauchi
K
K
Hara
S
S
Maeda
T
T
Kadowaki
T
T
Hansen
O
O
Pedersen
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*
D007328:Insulin; D011506:Proteins; C495324:VPS13C protein, human; D005947:Glucose
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18711367
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14663300
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18711366
Nat Genet. 2010 Feb;42(2):142-8
20081857
Diabetes Care. 1999 Sep;22(9):1462-70
10480510
Diabetes. 2007 Dec;56(12):3105-11
17827400
Diabetes Care. 2007 Feb;30(2):257-62
17259491
Nat Genet. 2010 Oct;42(10):864-8
20818381
Nat Genet. 2010 Feb;42(2):105-16
20081858
Diabetologia. 2010 Aug;53(8):1647-55
20419449
Diabetes. 2009 Jun;58(6):1450-6
19324940
Diabetes. 2010 May;59(5):1266-75
20185807