Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals

TY - JOUR

T1 - Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals

AU - Burgdorf, K S

AU - Gjesing, A P

AU - Grarup, N

AU - Justesen, J M

AU - Sandholt, C H

AU - Witte, D R

AU - Jørgensen, T

AU - Madsbad, S

AU - Hansen, T

AU - Pedersen, O

PY - 2012/1

Y1 - 2012/1

N2 - Aims/hypothesis Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting. Methods By applying an additive genetic model, 14 WHRassociated gene variants and 18 BMI-associated variants were investigated for their relationships with glucoserelated metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n=6,039). Results Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p=4.0×10 7) and increased disposition index of 5.6% (p=6.4×10 ?5). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p=0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p=0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p=0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p=0.00036) and 4.0% decrease in Matsuda index (p=2×10 ?4) Conclusions Our correlative findings from analyzing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.

AB - Aims/hypothesis Genome-wide association studies have identified novel WHR and BMI susceptibility loci. The aim of this study was to elucidate if any of these loci had an effect on quantitative measures of glucose homeostasis, including estimates of insulin release and insulin sensitivity in an epidemiological setting. Methods By applying an additive genetic model, 14 WHRassociated gene variants and 18 BMI-associated variants were investigated for their relationships with glucoserelated metabolic traits in treatment-naive individuals from the population-based Inter99 study sample (n=6,039). Results Of the variants associated with BMI, the QPCTL rs2287019 C allele was associated with an increased insulinogenic index of 7.4% per risk allele (p=4.0×10 7) and increased disposition index of 5.6% (p=6.4×10 ?5). The LRP1B rs2890652 C allele was associated with insulin resistance, showing a 3.3% increase (p=0.0011) using the HOMA-insulin resistance (HOMA-IR) index and a 2.2% reduction (p=0.0014) with the Matsuda index. Of the variants associated with WHR, LYPLAL1/SLC30A10 rs4846567 G allele carriers showed a 5.2% lower HOMA-IR (p=0.00086) in women, indicating improved insulin sensitivity. Female carriers of the VEGFA rs6905288 A allele were insulin resistant, with a 3.7% increase in HOMA-IR (p=0.00036) and 4.0% decrease in Matsuda index (p=2×10 ?4) Conclusions Our correlative findings from analyzing single-locus data suggest that some variation in validated BMI and WHR loci are associated with either increased or decreased insulin sensitivity and thereby potentially with metabolically healthy or metabolically unhealthy subsets of obesity. The results call for testing in larger study samples and for further physiological exploration of the possible metabolic implications of these loci.

U2 - 10.1007/s00125-011-2320-4

DO - 10.1007/s00125-011-2320-4

M3 - Journal article

C2 - 21953277

SN - 0012-186X

VL - 55

SP - 105

EP - 113

JO - Diabetologia

JF - Diabetologia

IS - 1

ER -