Endocrine Abstracts

Three independent studies identified SNPs in the first intron of the gene FTO as being strongly and consistently associated with BMI and/or obesity at significance levels (P=10⁻⁷ to P=10⁻³⁰) unobserved so far in genetics of obesity. The three studies estimated the putative effect around 1% of the total variance of BMI. So far, this represents the strongest effect for a common variant in obesity.

This result was replicated in at least 5 studies, either case–controls or general population of European and, less strongly Asian, descent. Interestingly, so far, the association has not been replicated in a 1100 African Americans cohort. However, both different allele frequencies and, for individual of African descent, lower linkage disequilibrium could explain this lack of replication.

Associated SNPs are located within a high LD block spanning 47 kb which includes exon 2 where both initial studies failed to find any mutation and thus the functional variant is not yet determined.

The FTO gene is ubiquitously expressed with a maximum in hypothalamus, which plays a major role in control of energy homeostasis. Contradictory results as to correlation of mRNA levels within hypothalamus in response to fasting rodent or correlation of FTO mRNA and obesity were found.

This gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase that could be involved in demethylation or DNA repair but its in vivo function is so far unknown.

Noticeably, another gene, RPGRIP1L (FTM) is close to associated SNPs and could be involved in obesity together with, or instead of FTO although initial KO study does not support this hypothesis.

Thus, at the time being, both the functional variation and the physiopathology of FTO action are partially unknown. I will provide an update of the ongoing research on this subject.