A Haplotype at the Adiponectin Locus Is Associated With Obesity and Other Features of the Insulin Resistance Syndrome
- Claudia Menzaghi12,
- Tonino Ercolino1,
- Rosa Di Paola2,
- Anders H. Berg3,
- James H. Warram1,
- Philipp E. Scherer3,
- Vincenzo Trischitta24 and
- Alessandro Doria1
- 1Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 2Unit of Endocrinology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- 3Department of Cell Biology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
- 4Department of Clinical Science, University La Sapienza, Rome, Italy
Adiponectin is a protein secreted by adipocytes that modulates insulin action. To assess whether variants of this gene contribute to the prevalence of insulin resistance in Caucasians, we genotyped 413 nondiabetic individuals for two single nucleotide polymorphisms (SNPs) at this locus. The two SNPs (45T→G and 276G→T) were chosen because of their association with type 2 diabetes in Japanese. Whereas each polymorphism was significantly associated with some correlate of insulin resistance, the haplotype defined by the two together was strongly associated with many components of the insulin resistance syndrome. Homozygotes for the risk haplotype had higher body weight (P = 0.03), waist circumference (P = 0.004), systolic (P = 0.01) and diastolic (P = 0.003) blood pressure, fasting glucose (P = 0.02) and insulin (P = 0.005) levels, homeostasis model assessment (HOMA) for insulin resistance (P = 0.003), and total to HDL cholesterol ratio (P = 0.01). Homozygotes also had significantly lower plasma levels of adiponectin (P = 0.03), independent of sex, age, and body weight. In an independent study group of 614 Caucasians, including 310 with type 2 diabetes, the risk haplotype was confirmed to be associated with increased body weight (P = 0.03) but not with type 2 diabetes per se. We conclude that variability at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome, but given the nature of the two SNPs, the risk haplotype is most probably a marker in linkage disequilibrium with an as yet unidentified polymorphism that affects plasma adiponectin levels and insulin sensitivity.
Address correspondence and reprint requests to Alessandro Doria, MD, PhD, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail:.
Received for publication 31 January 2002 and accepted in revised form 3 April 2002.
CV, coefficient of variation; HOMAIR, homeostasis model assessment for insulin resistance; IBW, ideal body weight; PPAR, peroxisome proliferator-activated receptor; SNP, single nucleotide polymorphism; TNF, tumor necrosis factor; UTR, untranslated region.