Endocrine Abstracts (2004) 7 S7

Uncovering the genetic causes of common obesity

P Froguel

Hammersmith Genome Centre and Genomic Medicine, Imperial College, London, UK; CNRS-Pasteur Institute, Lille, France.

Body Mass Index is an inheritable trait, and the intra familial relative risk to develop obesity is around 5. Genome Scans in Human provided a number obesity loci. The most replicated regions of linkage map on chromosome 2p, 7q and 10p but other potentially strong loci have been found on chromosome 4, 5, 6, 11, 12, 20..

The availability of extensive data bases of SNPs has made possible the positional cloning of obesity. We have recently investigated chromosome 10p obesity linked region and found some evidence for a contribution of SNPs in the promoter of the Glutamate Decarboxylase (Gad2) gene in morbid obesity. Our data suggest that increased activity of Gad2 modulates food intake behaviour through increasing the inhibitory neurotransmitter GABA pool. Remarkably, GAD2 SNPs also modulate the first phase of insulin secretion in several populations as well as the level of GAD65 antibodies.

We also conducted a genome-wide search for childhood obesity-associated traits. 431 microsatellite markers were genotyped in 506 subjects from 113 multiplex French Caucasian families. Our best peak of linkage (Lod = 4.1) maps on chromosome 6q, a region where QTLs for BMI, glucose and insulin values were found in 7 genome scans. In the 2.7 Mb region shared by all these GS, maps enpp1 gene encoding the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 or Cell Glycoproteine (PC-1). LD studies shows convincing evidence for a contribution of several SNPs in this gene to the genetic risk for obesity in children and also in adults obesity as well as for T2D. This enpp1 gene encoded enzyme has a pleiotropic effect and was previously suggested to be involved in insulin signalling as well as in bone calcification. However, other gene(s) in this region may also contribute to the observed linkage.

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