Gene variants in MC4R, SIRT1 and FTO are associated with severe obesity and metabolic impairment in Caucasians. We investigated whether common variants in these genes are associated with metabolic syndrome (MetS) in a large group of morbidly obese young adults from southern Italy. One thousand morbidly obese subjects (62% women, mean body mass index 46.5 kg/m(2), mean age 32.6 years) whose families had lived in southern Italy for at least 2 generations were recruited. Single-nucleotide polymorphisms (SNPs) rs12970134, rs477181, rs502933 (MC4R locus), rs3818292, rs7069102, rs730821, rs2273773, rs12413112 (SIRT1 locus) and rs1421085, rs9939609, 9930506, 1121980 (FTO locus) were genotyped by Taqman assay; blood parameters were assayed by routine methods; the Fat Mass, Fat Free Mass, Respiratory Quotient, Basal Metabolic Rate (BMR) and waist circumference were also determined. Binomial logistic regression showed that the TA heterozygous genotype of SNP rs9939609 in the FTO gene was associated with the presence of MetS in our population [OR (95% CI): 2.53 (1.16-5.55)]. Furthermore, the FTO rs9939609 genotype accounted for 21.3% of the MetS phenotype together with total cholesterol, BMR and age. Our results extend the knowledge on genotype susceptibility for MetS in relation to a specific geographical area of residence., (Copyright © 2014 Elsevier Ltd. All rights reserved.)