Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: association with subtype, body-mass index, severity and age of onset.
Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptin's effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.
Dardennes
Roland M
RM
Université Paris-Descartes, Faculté de Médecine, Hôpital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France.
Zizzari
Philippe
P
Tolle
Virginie
V
Foulon
Christine
C
Kipman
Amélie
A
Romo
Lucia
L
Iancu-Gontard
Dana
D
Boni
Claudette
C
Sinet
Pierre-Marie
PM
Thérèse Bluet
Marie
M
Estour
Bruno
B
Mouren
Marie-Christine
MC
Guelfi
Julien-Daniel
JD
Rouillon
Frédéric
F
Gorwood
Philip
P
Epelbaum
Jacques
J
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D054369:Agouti-Related Protein; D000483:Alleles; D000856:Anorexia Nervosa / Q000235:genetics* / Q000523:psychology*; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D054439:Ghrelin; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D036361:Peptide Hormones / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011569:Psychiatric Status Rating Scales
D054369:Agouti-Related Protein; D019208:Brain-Derived Neurotrophic Factor; D054439:Ghrelin; D036341:Intercellular Signaling Peptides and Proteins; D036361:Peptide Hormones; D004247:DNA