TY - JOUR
T1 - Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity
T2 - Evidence for a role of ACDC in diabesity
AU - Vasseur, F.
AU - Helbecque, N.
AU - Lobbens, S.
AU - Vasseur-Delannoy, V.
AU - Dina, C.
AU - Clément, K.
AU - Boutin, P.
AU - Kadowaki, T.
AU - Scherer, P. E.
AU - Froguel, P.
N1 - Funding Information:
Acknowledgements The authors wish to thank L. Olfert (Tib Mol-biol Syntheselabor, Germany) for the design of the LightCycler probes. This work was partly supported by EU-funded Grants GIFT QLG2-CT-1999-00546 and NUGENOB QLK1-CT-2000-00618, and by grants of the Association Française des Diabétologues de Langue Française (ALFEDIAM), of the Direction de la Recherche Clinique/ Assistance Publique-Hôpitaux de Paris and the Programme Hospi-talier de Recherche Clinique (AOM 96088) and of the Association Française des Diabétiques (AFD). F. Vasseur and N. Helbecque contributed equally to this work.
PY - 2005/5
Y1 - 2005/5
N2 - Aims/hypothesis: Morbid obesity (BMI>40 kg/m2) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. Methods: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6±7.4 kg/m2), 808 non-obese subjects (BMI<30 kg/m 2) and 493 obese subjects (30≤BMI<40 kg/m2). Results: Two 5′-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a 'low-level' haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5′-ACDC 'low-level' haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. Conclusions/ interpretation: These data clarify the contribution of the 5′-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.
AB - Aims/hypothesis: Morbid obesity (BMI>40 kg/m2) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. Methods: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6±7.4 kg/m2), 808 non-obese subjects (BMI<30 kg/m 2) and 493 obese subjects (30≤BMI<40 kg/m2). Results: Two 5′-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a 'low-level' haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5′-ACDC 'low-level' haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. Conclusions/ interpretation: These data clarify the contribution of the 5′-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.
KW - ACDC
KW - Adiponectin
KW - Genetics
KW - Insulin sensitivity
KW - Obesity
KW - PPARG
KW - Single nucleotide polymorphisms
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=20044384547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20044384547&partnerID=8YFLogxK
U2 - 10.1007/s00125-005-1729-z
DO - 10.1007/s00125-005-1729-z
M3 - Article
C2 - 15830179
AN - SCOPUS:20044384547
SN - 0012-186X
VL - 48
SP - 892
EP - 899
JO - Diabetologia
JF - Diabetologia
IS - 5
ER -