Resistin is a newly identified hormone secreted by adipocytes that inhibits insulin action on peripheral tissues. The aim of our study was to investigate whether genetic variability at this locus is associated with the risk of type 2 diabetes. By sequencing 32 subjects with type 2 diabetes, we identified 8 single nucleotide polymorphisms (SNPs) in the 5'-flanking region and introns of the resistin gene. Allele and genotype distributions were determined for all 8 SNPs in 312 cases with type 2 diabetes and 303 nondiabetic controls, all of Caucasian origin. No significant association with type 2 diabetes was found at any of the polymorphic loci. However, an interactive effect of genotype at SNP 6 (IVS2 + 181G-->A) and obesity was a significant determinant of type 2 diabetes risk in this population. The relative risk of diabetes for the A/A genotype was 4.8 (95% confidence interval, 1.1-21.0) in individuals above the median for body weight, but only 0.7 (95% confidence interval, 0.2-2.1) in those below the median. This difference between relative risks was significant (chi(2) = 4.5; P = 0.03). A similar, but much weaker, interaction with obesity was observed for SNPs in linkage disequilibrium with SNP6. In conclusion, resistin does not appear to be a major gene for type 2 diabetes. However, our data suggest a synergistic effect of sequence differences at the resistin locus and obesity on risk of type 2 diabetes. Further studies are needed to confirm this finding in other populations.