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Diabetologia. Author manuscript; available in PMC 2007 December 21.
Published in final edited form as:
PMCID: PMC2151140
EMSID: UKMS1225

Analysis of the obesity gene FTO in 14,803 type 1 diabetes cases and controls

To the Editor

Early weight gain in infancy, high nutrient intake and large body size in childhood have been associated with type 1 diabetes [1-4]. It has also been suggested that childhood weight gain accounts for the trend towards an earlier age at onset observed in type 1 diabetes [5]. The fat mass and obesity associated gene (FTO) region on chromosome 16q12 has recently been found to contribute to the risk of obesity [6]. Although the single nucleotide polymorphism (SNP) rs9939609 (T>A) in the fat mass and obesity associated gene (FTO) was originally found to be associated with type 2 diabetes (odds ratio 1.27, 95% CI 1.16-1.37; p = 5×10-8), this association was shown to be entirely mediated by the effect of FTO on obesity [6]. The FTO polymorphism was associated with an increased BMI of ~0.2 kg/m2 per allele in children aged 7 years (p = 3×10-5) up to an increase of ~0.4 kg/m2 at age 11 years [6]. The effect of the FTO gene variant on obesity, in particular on childhood obesity, makes it a good candidate to test whether a genetic predisposition to increased weight gain affects susceptibility to type 1 diabetes.

We analysed the FTO SNP rs9939609 in a cohort of 14,803 British type 1 diabetes subjects and controls of white ethnicity. The type 1 diabetes case group consists of 7,463 participants from the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory’s Genetic Resource Investigating Diabetes study (http://www-gene.cimr.cam.ac.uk/todd/, last accessed in June 2007) and 184 from the Oxford Regional Prospective Study [7]. All of the type 1 diabetes group were aged under 17 years at diagnosis. The control group, which is geographically matched to the case group, consists of 5,655 individuals from the British 1958 Birth Cohort (http://www.b58cgene.sgul.ac.uk/index.php, last accessed in June 2007) and 1,501 individuals from the UK Blood Services repository [8], all of whom are of white ethnicity. The controls include 95% of the 2,855 controls used by the Wellcome Trust Case-Control Consortium (http://www.wtccc.org.uk/, last accessed in June 2007) [8], as reported by Frayling et al. [6]. Genotyping was carried out using the TaqMan 5′ nuclease assay (Applied Biosystems, Warrington, UK). Given the reported minor allele (A) frequency (MAF) of 0.40 [6], our study had 99% power to exclude an effect with an OR >1.14 at α = 10-3. This α level can be considered appropriate assuming that the prior information concerning obesity being a factor in type 1 diabetes is true. Alternatively, assuming no prior information, on a genome-wide level, in which case an α level of 10-8 would be appropriate, our study has 99% power to exclude an effect with an OR >1.2. In this sample set we obtained a MAF of 0.39 for the A allele of rs9939609 (Table 1). The genotype distribution for this SNP was consistent with Hardy-Weinberg equilibrium in both the controls and the cases (p = 0.94). We found no evidence for an association between FTO and type 1 diabetes (OR 1.03, 95% CI 0.98-1.08; p = 0.26) (Table 1). We tested whether there was any association between FTO and the age at diagnosis of type 1 diabetes. In this test we treated age at diagnosis as a continuous variable and found no association (p = 0.85). We also analysed the frequencies of the rs9939609 genotypes in children stratified into the following groups according to age at diagnosis of type 1 diabetes: 0-5 years, 5-10 years and >10 years. The frequency of the AA genotype (the genotype most strongly associated with obesity) was almost identical (0.16) in all three age groups (Table 2).

Table 1
Association of the FTO gene SNP rs9939609 with type 1 diabetes in 7,647 type 1 diabetic individuals and 7,156 controls. We assumed a multiplicative model of effect
Table 2
Genotype frequency of the SNP rs9939609 in type 1 diabetes subjects stratified according to age at diagnosis

In this study we found that the FTO gene polymorphism rs9939609, which increases the risk of childhood obesity and type 2 diabetes [6], does not alter susceptibility to type 1 diabetes nor the age at which type 1 diabetes occurs, to any measurable extent, in this British population. Our results do not disprove the findings associating weight gain with type 1 diabetes [4], but indicate that FTO-mediated weight gain does not predispose individuals to type 1 diabetes as it does for type 2 diabetes.

Acknowledgements

This work was funded by the Wellcome Trust, the Juvenile Diabetes Research Foundation and the Medical Research Council. We acknowledge use of DNA from the British 1958 Birth Cohort collection (D. Strachan, P. Barton, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02. We also thank B. Widmer and H. Stevens and the JDRF/WT Diabetes and Inflammation Laboratory DNA team for collecting and preparing the type 1 diabetes case samples, and J. Hafler for help with genotyping.

Abbreviations

MAF
minor allele frequency
OR
odds ratio
SNP
single nucleotide polymorphism

Footnotes

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

References

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