Variation in the ESR1 and ESR2 genes and genetic susceptibility to anorexia nervosa

Abstract

There is significant evidence for genetic factors in the susceptibility to anorexia nervosa (AN). Previously genetic variation in the estrogen receptor 2 gene (ESR2) has been studied, however no strong evidence of association with AN has been found. In the present study variation in the estrogen receptor 1 (ESR1) and ESR2 genes was examined. Estrogen receptors have been localised to areas of the brain involved in behaviour and regulation of food intake. The anorexic effects of estrogen are accentuated by stress and thus it is postulated that variation in the estrogen receptors may contribute to the genetic susceptibility to AN in females. A cohort of 170 female, Caucasian AN sufferers and 152 female controls were typed for dinucleotide repeat polymorphisms in both ESR1 and ESR2 and two further SNPs at each locus. Variation at ESR1 was not associated with AN. However an association was found at the ESR2 locus with the heterozygous genotype of the G1082A polymorphism and AN but not with any of the other ESR2 polymorphisms analysed. Analysis of haplotypes at ESR1 and ESR2 showed no significant evidence of association with AN suggesting that the variability in ESR2 alone may contribute to the genetic susceptibility to AN. Molecular Psychiatry (2002) 7, 86-89. DOI: 10.1038/ sj/mp/4000929More than 90% of AN sufferers are female. It is generally accepted that the age of onset of AN shows a bimodal distribution 1 with one peak at or around the age of puberty in females when estrogen levels are dramatically increased. Estrogen receptors in the brain colocalise with corticotrophin releasing factor (CRF) 2 suggesting an interaction between estrogen and CRF may modulate the hypothalamic pituitary adrenal (HPA) axis. The disruption of the HPA axis in AN sufferers cannot be wholly attributed to the effects of semi-starvation 3 and the HPA axis is also elevated in response to stress. 4,5 In rodents and primates high estrogen levels are known to have an inhibitory effect on food intake. 6 This led us to postulate that estrogen may be involved in the genetic disposition to AN. Estrogen interacts in both the periphery and the central nervous system via at least two different estrogen receptors (ESR1 and ESR2). 7,8 Previously Rosenkranz et al reported genetic variations in the ESR2 (ESR-beta) gene in probands of different weight extremes (including patients with AN and bulimia nervosa) and reported suggestive evidence of an association with susceptibility to AN. 9 ESR1 has been shown to play a role in behaviour in mice 10 and more recently variants of the ESR1 gene have been implicated in anxiety. 11 As it has previously been suggested that anxiety may accentuate the anorexic effects of estrogen, 12 we postulate that the interaction of stress and estrogen may modulate the HPA axis in the pathogenesis of anorexia nervosa. Both ESR1 and 2 are localised to the amygdaloid complex, 13 an area known to be critical in the control of emotions. These receptors are known to form heterodimers in vitro 14 and therefore this study aimed to inv...

Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status

“…[14][15][16][17][18][19][20][21] Several studies demonstrated that the effect of ERT/HRT on lipid levels or atherosclerosis progression in postmenopausal women may differ according to genotypes of genes with important role in lipid metabolism or CVD development, such as apolipoprotein E, [22][23][24] hepatic lipase 25 and myeloperoxidase. 26 Other studies have also shown associations between ESR1 polymorphisms and lipid levels, CVD disease or some vessels' angiographic complications.…”

Estrogen Receptors in Glucose Homeostasis

“…Polymorphisms of the ESR1 gene can also affect lipoprotein metabolism (Lamon-Fava et al, 2010). ESR2 polymorphisms have been associated with anorexia nervosa, bulimic disease and premature coronary artery disease (Eastwood et al, 2002;Nilsson et al, 2004;Peter et al, 2005). ERs share a common structure with the other members of the nuclear receptor family.…”

A review and primer of molecular genetic studies of anorexia nervosa

“…Bergen et al (41) Association Yes SERT, NET Urwin et al (37) TDT and Association No OPRD1 Bergen et al (41) Association Yes ER a Eastwood et al (48) Association No…”

“…The anorectic effects of estrogens have been noted for decades 46,47 and the estrogen receptor b (ERb) gene has shown associations with both AN and BN. 48,49 This gene is also located on chromosome 14, which was found to be in significant linkage with BN. 43 Interestingly, serotonin receptors are regulated by estrogen with estrogen affecting serotonin gene transcription.…”