FTO gene SNPs associated with extreme obesity in cases, controls and extremely discordant sister pairs

Obesity has become the most common human disorder and it poses a serious threat to health and quality of life through its association with diabetes, hypertension, cardiovascular disease, and cancer. Rates have been increasing during the past century, particularly during the past two decades, and show no sign of leveling off. The average body mass index (BMI, weight in kg/height in m²) of the U.S. population is well into the overweight range (BMI = 28.1 kg/m²), more than 30% of the people in the United States are obese (BMI ≥ 30 kg/m²) and more than 64% are overweight (BMI > 25 kg/m²)[1]. Recent predictions are for a reduction in life expectancy and quality of life for the next generation [2].

Recently, a genome wide association study revealed an association with a common variant in single nucleotide polymorphisms located in intron 1 of FTO, a gene with previously unknown function located in chromosome region 16q12.2 [3]. A second study found associations with nearby SNPs[4]. The 3 primary SNPs, rs9939609 in the Frayling et al. [3] study and rs1421085 and rs17817449 in the Dina et al study[4], are located within 20 kb and are in strong linkage disequilibrium (LD). The FTO association is notable because of its strength and the consistency of replication across several samples, both within and between studies. For example, FTO associations with physical activity related body fat accumulation [5] and obesity related traits [6, 7] were found in studies having large sample sizes. To date, the obesity association has been found only in Europeans or individuals of European descent. FTO was not associated with obesity in Han Chinese [8] or with six Oceanic populations [9]. Field et al. [10] tested FTO gene variants in type 1 diabetes cases and controls, however, no significant association was found. The association with type II diabetes is mediated entirely by BMI [3].

In this report we examined three SNPs to determine whether FTO variability could distinguish between extremely obese cases and thin controls. In addition, we extended our investigation to examine extremely discordant sister pairs, because the shared genetic background may be useful in future attempts to identify functional variants.

The results of this study strongly replicate and extend those from previous reports of an association between FTO and human obesity. The effect size was large, with odds ratios to 1.69–1.75 in cases and controls and 1.46–1.65 in discordant sisters. These values are similar to those reported previously [3, 4]. The consistency and strength of the associations along with the high frequencies of the risk alleles/haplotype among extremely obese individuals suggest the effects of this gene, while still unknown, are common and pervasive. Given the history of non-replications for other gene associations, the consistency and strength of the replication is particularly notable. Moreover, because of the very large sample sizes in the original studies [3, 4] one might reasonably have expected it would be difficult to find the association with moderate sample sizes like those of the current study. However, the effects are quite strong and detectible even in a relatively small sample of discordant sisters.

Extreme sampling from both tails of the phenotypic distribution is uncommon, because the screening process in sample selection requires much more effort. However, the increase in power to detect associations is substantial [13]. The design should select for both risk and protective variation in cases and controls, respectively The case-control sample of the current study is a powerful one and likely played a role in the strong replication, even though it is only of moderate size.

The use of extremely discordant sibling pairs is particularly uncommon because of the difficulty and expense in accruing such samples. However, pairs that differ in phenotype can increase power to identify associations, particularly when they also differ in genotype [14]. The results from this study indicate that FTO can have a substantial effect on obesity risk between individuals close in age, having similar rearing environments, and sharing half their genes identical by descent. While the sample sizes for discordant siblings may be too small for definitive conclusions, they are highly significant, consistent with other results, and can be particularly useful in isolating causative sequence variability once an overall association has been identified.

Although the role of FTO or nearby genes in susceptibility to obesity remains unknown, several recent studies have begun to shed light on its function. For example, FTO is highly expressed in hypothalamic nuclei that control eating behavior [15]. An intriguing observation is that it catalyzes Fe(II)- and 2OG- dependent DNA demethylation [15], although the role of FTO related DNA methylation in obesity is unknown. Further studies are needed to clarify the functional relationship of FTO with obesity susceptibility.

These results suggest common variability in FTO is associated with increased obesity risk or resistance and may in part account for differences between closely related individuals.