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Aim: The present study investigated the association of six variants—rs9940128, rs7193144, and rs8050136 (in intron 1), rs918031 and rs1588413 (in intron 8), and rs11076023 (3′ untranslated region)—across three regulatory regions of the fat mass and obesity-associated (FTO) gene with obesity and type 2 diabetes mellitus (T2DM) in a South Indian population. Methods: Unrelated study subjects (n = 1,852; 1,001 normal glucose-tolerant [NGT] controls and 851 cases [T2DM]) were randomly selected from the Chennai Urban Rural Epidemiological Study (CURES). Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism method, and 20% of samples were sequenced to validate the genotypes obtained. Haplotype analysis was also carried out. Results: The three polymorphisms rs9940128 A/G, rs1588413 C/T, and rs11076023 A/T of the FTO gene were associated with T2DM in our study population. The rs8050136 C/A variant was associated with obesity, and its association with T2DM was also mediated through obesity. The rs1588413 C/T variant showed an association with obesity in the total study subjects, but when the NGT subjects alone were analyzed, the association with obesity was lost. The haplotype ACCTCT confers a lower risk of T2DM in this South Indian population. Conclusions: Among South Indians, the rs9940128 A/G, rs11076023 A/T, and rs1588413 C/T variants of the FTO gene were associated with T2DM, whereas the rs8050136 C/A variant was associated with obesity. [ABSTRACT FROM AUTHOR]