TY - JOUR
T1 - Common genetic determinants of glucose homeostasis in healthy children
T2 - the European Youth Heart Study
AU - Kelliny, Clara
AU - Ekelund, Ulf
AU - Andersen, Lars Bo
AU - Brage, Soren
AU - Loos, Ruth J F
AU - Wareham, Nicholas J
AU - Langenberg, Claudia
PY - 2009/12/1
Y1 - 2009/12/1
N2 - 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. RESEARCH DESIGN AND 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.
AB - 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. RESEARCH DESIGN AND 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.
KW - Adolescent
KW - Blood Glucose
KW - Child
KW - Diabetes Mellitus, Type 2
KW - European Continental Ancestry Group
KW - Fasting
KW - Female
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Glucose
KW - Glucose-6-Phosphatase
KW - Homeostasis
KW - Humans
KW - Insulin
KW - Insulin Resistance
KW - Insulin-Secreting Cells
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Protein-Serine-Threonine Kinases
KW - Receptor, Melatonin, MT1
KW - Reference Values
U2 - 10.2337/db09-0374
DO - 10.2337/db09-0374
M3 - Journal article
C2 - 19741166
SN - 0012-1797
VL - 58
SP - 2939
EP - 2945
JO - Diabetes
JF - Diabetes
IS - 12
ER -