In this study, we confirmed that the SNP rs9939609 was associated with higher BMI and obesity risk (1
) in men and women from two independent U.S. cohorts. Frayling et al. (1
) observed that the FTO
genotype–associated difference in BMI occurred as early as 7 years old. We observed associations between FTO
SNP and high BMI in early adulthood. The genetic effects were constant across different ages in women but tended to decrease at older ages in men. The mechanisms underlying this observation are not clear. A longitudinal twin study suggests that the genetic components regulating body weight may vary throughout life (28
) and decrease with advanced age (29
). Adiposity loss with age may partly explain the reduction in association at senior age. In addition, environmental influences accumulate with age and likely exert stronger influences on later BMI. It appears that the decreasing trend of BMI with advanced age is more pronounced in men than in women, but the test for interaction between sex and FTO
was not statistically significant.
In women, rs9939609 was associated with greater risk of type 2 diabetes. Adjustment for BMI abolished the association. This finding is consistent with the observations from recent GWA studies (2
), supporting the idea that obesity mediates the effects of FTO
variant on the development of type 2 diabetes.
Adipose tissue acts as endocrine organ through secreting hormone-like adipokines, which mediate the effects of obesity on various metabolic disorders (31
). Adiponectin is the most abundant adipokine in the circulation (32
). Adiponectin improves insulin action and metabolism of glucose and lipids (33
). Low blood adiponectin levels have been related to increased risk of obesity and diabetes (35
). Our data indicated that low adiponectin levels associated with the risk allele A were secondary to the changes in BMI and may partly mediate the genetic effects on diabetes risk. The association between FTO
SNP and adiponectin was observed in diabetic patients. Future studies are warranted to replicate the findings in the general population.
Little is known about the function of FTO
gene. Our data comparing both human and mouse genes confirm high expression of FTO
gene in brain (1
). Gerken et al. (37
) recently demonstrated that FTO
was highly expressed in arcuate, paraventricular, dosomedial, and ventromedial nuclei. Of note, all of these sites are of critical importance in controlling energy balance. These data suggest FTO
gene may affect the neuroregulation of energy balance. In addition, FTO
expression was high in heart, kidney, and adipose tissues (particularly brown fat in mice).
The expression of FTO
was moderately increased in adipocytes compared with preadipocytes and was substantially reduced in white adipose tissues of obese, diabetic db
mice, indicating that it may play a role in adipocyte function but not adipogenesis. The mechanism underlying the reduced expression of FTO
in adipocytes from the genetic models with direct interruptions of the leptin axis (db
mice) is not clear. The data suggest that FTO
is likely a part of the pathway mediating the neuroregulation (e.g., leptin) of energy metabolism in adipose tissue, and blocking the leptin signal may inhibit the downstream changes in adipose tissue that induce the expression of FTO
. Furthermore, FTO
was found to be expressed in leukocytes and was drastically upregulated in macrophages stimulated with IFN-γ and LPS. Given that metabolic dysregulation is recognized as a state of chronic inflammation (38
), it is possible that FTO
is a molecular link between metabolism and inflammation in the pathogenesis of obesity-related metabolic diseases.
SNP rs9939609 is highly correlated with many other SNPs within a 47-kb region encompassing parts of the first two introns and exon 2 of FTO
gene. Sequencing the chromosomes did not result in clear candidate functional variants in the FTO
coding region, minimal splice sites, or 3′-untranslated region (1
). Further work is warranted to explore the genetic mechanism underpinning the observed associations.
Several limitations need to be acknowledged. Population stratification, mostly arising from either ethic admixture or genetic substructure within an ethnically homogenous group, may cause spurious associations. However, neither is likely to explain the associations observed in the present study. Our study populations are highly homogeneous by including only European whites. In addition, there is no evidence showing regional difference in rs9939606 across European countries (1
The participants in our study do not represent random samples of U.S. men and women. However, major cohort studies, such as the Framingham Heart Study, have also not relied on national samples. Clearly, data validity is the chief prerequisite that must be fulfilled before the results can be generalized. In previous analyses, the observed genetic and environmental associations for obesity, type 2 diabetes, coronary heart disease, and other diseases in our cohorts are very similar to those found in other broadly based U.S. populations (40
). Nonetheless, the findings in the present study need to be replicated in other ethnic groups.
Adiposity measures were self-reported in our cohorts. However, self-reported information has been reliably validated, with a high correlation with technician-measured variables (21
). In addition, previous analyses in NHS and HPFS have demonstrated that self-reported BMI and waist circumference strongly predicted various chronic diseases (40
We examined only one SNP, rs9939609, which was reported by the original GWA study (1
). Several other SNPs were associated with obesity in subsequent studies (4
), but these SNPs are all in strong to perfect linkage disequilibrium with rs9939609. Thus, genotyping of these SNPs would have been redundant.
In conclusion, we confirmed associations between the FTO SNP rs9939609 and higher obesity risk. Our data suggest that the genetic association for obesity may decline at older age. In addition, the genetic variant may affect circulating adiponectin levels through the changes in BMI. The expression of FTO gene was reduced in adipocytes from db/db mice. Little is known about the function of FTO gene, and thus, further investigation is warranted to identify the causal genetic variants and potential mechanisms underlying the observed genetic associations.