Association between a marker in the UCP-2/UCP-3 gene cluster and genetic susceptibility to anorexia nervosa

Abstract

Anorexia nervosa (AN) is an enigmatic syndrome affecting approximately 0.1% of the at risk population in the UK which equates to approximately 70 000 sufferers. Data from a number of studies have demonstrated the heritability of this disorder, however it is only in the last few years that studies have begun to determine the involvement of particular candidate genes in this genetic predisposition. In the current study we have used classical case-control association analysis to determine whether two highly polymorphic microsatellite markers, located within a 3-cM region of the UCP-2/UCP-3 locus, show involvement of this region of the human genome in the predisposition to AN. Analysis of a cohort of 170 female Caucasian anorexia nervosa sufferers and 150 normal female controls shows evidence of association with the marker D11S911 but not D11S916. Allele 13 of the marker D11S911 is significantly over represented in the anorexia nervosa population suggesting that a mutation in linkage disequilibrium with this locus may form part of the genetic component of AN. Further work is now required to try to reproduce these data in a second independent cohort and to further characterise this region of the human genome.Recently, there has been an upsurge of interest in the genetics of anorexia nervosa (AN). There is now more acceptance that this disorder, once thought of purely in psycho-social terms, has a sizeable genetic component. Data from Germany have failed to show association with a number of candidate loci. 1-3 However, the list of genes that might theoretically play a role in this disorder is far from exhausted.It has been suggested that AN may involve an aberration in the serotonergic system. Recent data from Collier and colleagues 4 demonstrate a putative association between a polymorphism in the promoter region of the 5-HTR 2A gene and genetic predisposition to AN. However, we 5 and others 1 have been unable to confirm this initial observation. The debate regarding the involvement of this locus in the genetic predisposition to AN is still unclear and two further small studies also claim association at this locus. 6,7 In the current study we focused on two further candidates, namely UCP-2 and UCP-3. The protein products of these genes are ubiquitously expressed and are thought to have a role in the control of energy expenditure and metabolic adaptation during fasting. 8 Several studies, including that of Moukaddem and colleagues, 9 describe the difficulty of inducing weight gain in AN patients, and that unusually high energy intakes are required to maintain a normal weight after refeeding. Indeed, these patients seem to maintain a low body mass with relative ease. Given the involvement of UCP-2 and UCP-3 in thermogenesis, the two corresponding genes are plausible candidates for a role in the genetic susceptibility to AN.The genes for UCP-2 and UCP-3 co-localise to a 10.5 cR 3000 , or ෂ3-cM, region of human chromosome 11q13. Two highly polymorphic microsatellite markers have been identified within this region and hav...

Analysis of microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa

“…The distribution of alleles we found for D11S916 was similar to that observed by Campbell et al, 7 but D11S911 was markedly different. Campbell et al reported 17 alleles whereas we found 19, ranging from 159 bp to 215 bp on 666 chromosomes.…”

“…Campbell et al 7 reported allelic association between a microsatellite marker at the UCP2/UCP3 locus on chromosome 11q13 and anorexia nervosa. Resting metabolic rate (RMR) is linked to the uncoupling protein 2/3 (UCP2/3) locus on chromosome 11q13 8 and polymorphisms within UCP2 are associated with metabolic rate.…”

“…We sequenced a homozygote for the 159-bp allele (data not shown), and confirmed that it is a true allele of D11S911. Although Campbell et al 7 did not report the base-pair sizes of their alleles, we assume that their most common allele, named allele 4, corresponds to a size of 183 bp based on the graphical distribution shown. Thus we think that Campbell et al 7 have inadvertently excluded the short common allele from their analysis.…”

The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP

“…A linkage to this locus was also observed in patients with anorexia nervosa [193]. Kaisaki et al [155] localized the UCP2 and UCP3 genes to a region of rat chromosome 1 linked to glucose intolerance and adiposity in the Goto-Kakizaki type II diabetic rat.…”

Activities of respiratory chain complexes in isolated platelets in females with anorexia nervosa

“…For example, an association between a specific polymorphism in the uncoupling proteins UCP-2/UCP-3 gene cluster and anorexia nervosa has been described. 11 The aim of our study was to analyze the function of energetic metabolism in females with anorexia nervosa directly by the measurement of activities of respiratory chain complexes in isolated platelets.…”