Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity:: evidence for a role of ACDC in diabesity

Aims/hypothesis: Morbid obesity (BMI > 40 kg/m(2)) 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 collagendomain-containing (ACDC) gene (-11,391G > A, -11,377C > G, + 45T > G and + 276G > T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12A1a SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6 +/- 7.4 kg/m(2)), 808 non-obese subjects (BMI < 30 kg/m(2)) and 493 obese subjects (30 <= BMI < 40 kg/m(2)). 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 Pro12A1a 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.