FTO function may encompass more than body mass

By Helen Albert, Senior medwireNews Reporter

medwireNews: Three variants in the fat mass and obesity associated gene (FTO) are associated with significant predisposition to melanoma, show findings published in Nature Genetics.

Notably, all the melanoma-associated FTO single nucleotide polymorphisms (SNPs) were located in intron 8 of the gene and were not associated with body mass index (BMI), unlike all the previously discovered disease-associated FTO SNPs located in intron 1.

"This is the first time to our knowledge that any variant in FTO has been shown to have a replicable association with a trait without being associated with BMI," say lead author Mark Iles (University of Leeds, UK) and colleagues.

The team adds that the results suggest that "FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity."

The researchers carried out a genome-wide association study in people of European or Israeli ancestry, including 1373 people with melanoma and 3571 controls. Overall, 2.6 million SNPs were genotyped and tested for links with melanoma.

The strongest association with melanoma in an area of the genome not previously associated with the disease was for the SNPs rs16953002 and rs12596638 located in FTO intron 8. Each copy of the A (risk) allele for each SNP carried a significant 33% and 34% increased risk for melanoma, respectively.

These associations remained significant in replication cohorts, with risk increases per A allele carried ranging from 14% to 34%.

Iles and team carried out further analysis to evaluate whether rs16953002 or rs12596638 were associated with BMI in the 37% of melanoma cases and 59% of controls for whom BMI data was available, but no relationship was observed.

"It may be that the melanoma-associated SNPs are in LD [linkage disequilibrium] with functional SNPs outside of FTO, but given the low level of LD in the region this seems unlikely," write the authors.

As well as being the first replicable disease-associated variants in FTO not linked to BMI, this is the first time that any disease-associated variants have been found in FTO located outside intron 1, which "will be of interest to researchers in the fields of both cancer genetics and obesity research," they conclude.

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