Skip to main content
Erschienen in: Diabetologia 1/2012

01.01.2012 | Article

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

verfasst von: K. S. Burgdorf, A. P. Gjesing, N. Grarup, J. M. Justesen, C. H. Sandholt, D. R. Witte, T. Jørgensen, S. Madsbad, T. Hansen, O. Pedersen

Erschienen in: Diabetologia | Ausgabe 1/2012

Einloggen, um Zugang zu erhalten

Abstract

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 WHR-associated gene variants and 18 BMI-associated variants were investigated for their relationships with glucose-related 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 analysing 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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
2.
Zurück zum Zitat Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCrossRef Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCrossRef
3.
Zurück zum Zitat Loos RJ, Lindgren CM, Li S et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775PubMedCrossRef Loos RJ, Lindgren CM, Li S et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775PubMedCrossRef
4.
Zurück zum Zitat Speliotes EK, Willer CJ, Berndt SI et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948PubMedCrossRef Speliotes EK, Willer CJ, Berndt SI et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948PubMedCrossRef
5.
Zurück zum Zitat Heid IM, Jackson AU, Randall JC et al (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949–960PubMedCrossRef Heid IM, Jackson AU, Randall JC et al (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42:949–960PubMedCrossRef
6.
Zurück zum Zitat Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE (2006) Weight, shape, and mortality risk in older persons: elevated waist-hip ratio, not high body mass index, is associated with a greater risk of death. Am J Clin Nutr 84:449–460PubMed Price GM, Uauy R, Breeze E, Bulpitt CJ, Fletcher AE (2006) Weight, shape, and mortality risk in older persons: elevated waist-hip ratio, not high body mass index, is associated with a greater risk of death. Am J Clin Nutr 84:449–460PubMed
7.
8.
Zurück zum Zitat Thorleifsson G, Walters GB, Gudbjartsson DF et al (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24PubMedCrossRef Thorleifsson G, Walters GB, Gudbjartsson DF et al (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24PubMedCrossRef
9.
Zurück zum Zitat Willer CJ, Speliotes EK, Loos RJ et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34PubMedCrossRef Willer CJ, Speliotes EK, Loos RJ et al (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41:25–34PubMedCrossRef
10.
Zurück zum Zitat Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C (2003) A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil 10:377–386PubMedCrossRef Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C (2003) A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil 10:377–386PubMedCrossRef
11.
Zurück zum Zitat Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419PubMedCrossRef Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419PubMedCrossRef
12.
Zurück zum Zitat Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470PubMedCrossRef Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470PubMedCrossRef
13.
Zurück zum Zitat Hansen T, Drivsholm T, Urhammer SA et al (2007) The BIGTT test: a novel test for simultaneous measurement of pancreatic beta-cell function, insulin sensitivity, and glucose tolerance. Diabetes Care 30:257–262PubMedCrossRef Hansen T, Drivsholm T, Urhammer SA et al (2007) The BIGTT test: a novel test for simultaneous measurement of pancreatic beta-cell function, insulin sensitivity, and glucose tolerance. Diabetes Care 30:257–262PubMedCrossRef
14.
Zurück zum Zitat Saxena R, Hivert MF, Langenberg C et al (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142–148PubMedCrossRef Saxena R, Hivert MF, Langenberg C et al (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142–148PubMedCrossRef
15.
Zurück zum Zitat Jansen J, Karges W, Rink L (2009) Zinc and diabetes–clinical links and molecular mechanisms. J Nutr Biochem 20:399–417PubMedCrossRef Jansen J, Karges W, Rink L (2009) Zinc and diabetes–clinical links and molecular mechanisms. J Nutr Biochem 20:399–417PubMedCrossRef
16.
Zurück zum Zitat May P, Woldt E, Matz RL, Boucher P (2007) The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med 39:219–228PubMedCrossRef May P, Woldt E, Matz RL, Boucher P (2007) The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med 39:219–228PubMedCrossRef
17.
Zurück zum Zitat Silha JV, Krsek M, Sucharda P, Murphy LJ (2005) Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 29:1308–1314CrossRef Silha JV, Krsek M, Sucharda P, Murphy LJ (2005) Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond) 29:1308–1314CrossRef
18.
Zurück zum Zitat Garcia de la Torre N, Rubio MA, Bordiu E et al (2008) Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab 93:4276–4281PubMedCrossRef Garcia de la Torre N, Rubio MA, Bordiu E et al (2008) Effects of weight loss after bariatric surgery for morbid obesity on vascular endothelial growth factor-A, adipocytokines, and insulin. J Clin Endocrinol Metab 93:4276–4281PubMedCrossRef
19.
Zurück zum Zitat Staiger H, Machicao F, Kantartzis K et al (2008) Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes. PLoS One 3:e3019PubMedCrossRef Staiger H, Machicao F, Kantartzis K et al (2008) Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes. PLoS One 3:e3019PubMedCrossRef
20.
Zurück zum Zitat Lindgren CM, Heid IM, Randall JC et al (2009) Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508PubMedCrossRef Lindgren CM, Heid IM, Randall JC et al (2009) Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508PubMedCrossRef
Metadaten
Titel
Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals
verfasst von
K. S. Burgdorf
A. P. Gjesing
N. Grarup
J. M. Justesen
C. H. Sandholt
D. R. Witte
T. Jørgensen
S. Madsbad
T. Hansen
O. Pedersen
Publikationsdatum
01.01.2012
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 1/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2320-4

Weitere Artikel der Ausgabe 1/2012

Diabetologia 1/2012 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.