Circulating high molecular weight adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family‐based study

Abstract

Abstract. Menzaghi C, Salvemini L, Paroni G, De Bonis C, Mangiacotti D, Fini G, Doria A, Di Paola R, Trischitta V (IRCCS ''Casa Sollievo della Sofferenza'', San Giovanni Rotondo (FG), Italy, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA, ''Sapienza'' University; IRCCS Casa Sollievo della Sofferenza-Mendel Institute, Rome, Italy). Circulating HMW adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family-based study. J Intern Med 2010; 267: 287-294.Objective. Reduced circulating adiponectin levels contribute to the aetiology of insulin resistance. Adiponectin circulates in three different isoforms: high molecular weight (HMW), medium molecular weight (MMW) and low molecular weight (LMW) isoforms. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits.Methods. In a family-based sample of 640 nondiabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three single nucleotide polymorphisms (SNPs) in the ADI-POQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test the association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits.Results. All isoforms were highly heritable (h 2 = 0.60-0.80, P = 1.0 · 10 )13 -1.0 · 10 )23 ). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2-9%, P = 1.0 · 10 )3 -1.0 · 10 )5 ). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (P = 3.0 · 10 )4 and 2.0 · 10). Significant genetic correlations (P = 1.0 · 10 )2 -1.0 · 10 )5 ) were observed between HMW adiponectin and fasting insulin, homeostasis model assessment of insulin resistance, HDL cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations.Conclusion. Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistancerelated traits and involves, but is not limited to, the ADIPOQ locus.

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

“…This association also remained significant in a model comprising all five SNPs (p=0.035). As previously reported, rs17300539 is also strongly associated with HMW adiponectin (β=0.26±0.064, p=4.8×10 −5 ) and explains almost 10% of its variance in our sample [32].…”

“…After adjusting for age, age squared, sex, smoking habits and physical exercise, ACR and HMW adiponectin (the latter as previously described [32]) were moderately (h 2 =0.20±0.09, p=0.006) and highly (h 2 =0.79±0.06, p=1.0×10…”

“…cystatin C-GFR≥60 ml/min) from 233 families living in the Gargano area of Italy (an homogeneous geographical area in central-east Italy) [29] and examined them as previously described [30][31][32]. All study participants were not being treated with medications known to interfere with glucose homeostasis, lipid profile and blood pressure, or with those known to modulate adiponectin and ACR levels.…”

“…Measurements Serum HMW, MMW and LMW adiponectin concentrations were measured by ELISA (Alpco, Salem, NH, USA) as previously described [32].…”

“…The HOMA insulin resistance index (HOMA IR ) was calculated as fasting serum insulin (pmol/l)×fasting plasma glucose (mmol/l)/135 [31,32].…”