Common genetic determinants of glucose homeostasis in healthy children: the European Youth Heart Study.
OBJECTIVE
The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children.


METHODS
Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, and Chr 11p12).


RESULTS
Strongest associations were observed for G6PC2 and MTNR1B, with mean fasting glucose levels (95% CI) being 0.084 (0.06-0.11) mmol/l, P = 7.9 x 10(-11) and 0.069 (0.04-0.09) mmol/l, P = 1.9 x 10(-7) higher per risk allele copy, respectively. A similar but weaker trend was observed for GCK (0.028 [-0.006 to 0.06] mmol/l, P = 0.11). All three variants were associated with lower beta-cell function (HOMA-B P = 9.38 x 10(-5), 0.004, and 0.04, respectively). SLC30A8 (rs13266634) was the only type 2 diabetes variant associated with higher fasting glucose (0.033 mmol/l [0.01-0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 x 10(-17)), with mean levels of 5.34 versus 4.91 mmol/l comparing children with seven alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants.


CONCLUSIONS
The effects of common polymorphisms influencing fasting glucose are apparent in healthy children, whereas the presence of multiple risk alleles amounts to a difference of >1 SD of fasting glucose.
Kelliny
Clara
C
Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, Institute of Metabolic Science, Cambridge, U.K.
Ekelund
Ulf
U
Andersen
Lars Bo
LB
Brage
Soren
S
Loos
Ruth J F
RJ
Wareham
Nicholas J
NJ
Langenberg
Claudia
C
D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism*; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005215:Fasting; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000081410:Germinal Center Kinases; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D044122:Receptor, Melatonin, MT1 / Q000235:genetics; D012016:Reference Values; D044465:White People / Q000235:genetics*
D001786:Blood Glucose; D000081410:Germinal Center Kinases; D007328:Insulin; D044122:Receptor, Melatonin, MT1; D017346:Protein Serine-Threonine Kinases; D005952:Glucose-6-Phosphatase; C492194:G6PC2 protein, human; D005947:Glucose