Our study of FTO as a candidate gene for MetS in a sample from multiple non-Caucasian geographical ancestries showed 1) significant association with the FTO gene, with rs9939609 A allele carriers, particularly males, having an increased risk of MetS (carrier OR 1.23, 95% CI 1.01 to 1.50; P = 0.036) (Table 2); and 2) this association was related to higher proportion of subjects with depressed HDL cholesterol and a trend towards increased waist circumference. Similar trends were observed for the NCEP ATP III definition of MetS.
This is the first report of an association between the FTO rs9939609 A allele and MetS. Furthermore, it extends the association of this allele beyond Caucasian samples. Although the observation may help understand the molecular etiology of MetS, this association requires replication in larger studies, considering the possibility of a spurious association due to population stratification or another such limitation . Despite considerations regarding sample size however, the results reaffirm the established association between the FTO rs9939609 A allele with obesity in past findings [8–11]. However, MetS is a complex disorder, and only a few of the previously associated genes, such as APOC3 and PPARG, have been replicated in more than one study sample . Aside from the need to replicate the FTO association in other larger study samples, the mechanism underlying the association also needs to be investigated. The mechanism underlying the association may be related to: 1) a direct function of FTO  or 2) linkage disequilibrium of the tested variant with another causative change in a gene near the FTO locus.
Analysis of the overall sample indicated that significantly more FTO rs9939609 A allele carriers met the MetS criteria for depressed HDL cholesterol (P = 0.0089) than non-carriers. In addition, values were close to significance also for increased waist circumference (P = 0.080) and increased BMI (P = 0.060) among A allele carriers (Table 2). This indicates that the association of the FTO rs9939609 A allele with the MetS was related in part to both the obesity component, but also the HDL component, suggesting that this genetic marker may have a broader relationship with individual components of this complex trait.
Although the meta-analysis across the four non-Caucasian study populations showed an association between MetS and the common rs9939609 SNP in FTO, analyses by individual ethnic populations indicated a significant increased risk for MetS only among the South Asians (IDF definition) and Greenland Inuit (NCEP ATP III definition). Thus, the overall association is primarily due to these two populations, with little influence from the Chinese and Oji-Cree. Again, replication of the FTO association in other larger study samples is essential for clarification. Further evidence against an association for the Chinese can be found in a recent study of 3,210 unrelated Chinese Han subjects from Shanghai and Beijing where no association found between the rs9939609 SNP and obesity .
In summary, we report an association between MetS and the common rs9939609 SNP in FTO. The observed consistent association between MetS and FTO in a non-Caucasian multi-ethnic study group, including populations which differ considerably in MetS prevalence, strengthens the likelihood that the FTO locus is related to obesity and MetS. Future replication of this association in larger sized samples and devising functional molecular studies will further enhance the validity of association and the causative relationship between the FTO variant and MetS.