Family and Population-Based Studies of Variation within the Ghrelin Receptor Locus in Relation to Measures of Obesity

Abstract

BackgroundThe growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight among Whites.Methodology/Principal FindingsIn a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity. None of these analyses revealed consistent association with measures of obesity. A -151C/T promoter mutation in the GHSR was found in two unrelated obese patients. One family presented with complete co-segregation, but the other with incomplete co-segregation. The mutation resulted in an increased transcriptional activity (p<0.02) and introduction of a specific binding for Sp-1-like nuclear extracts relative to the wild type. The -151C/T mutation was genotyped in the 15,854 Danes with a minor allele frequency of 0.01%. No association with obesity in carriers (mean BMI: 27±4 kg/m2) versus non-carriers (mean BMI: 28±5 kg/m2) (p>0.05) could be shown.Conclusions/SignificanceIn a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related traits. A rare functional GHSR promoter mutation variant was identified, yet there was no consistent relationship with obesity in neither family- nor population-based studies.

Ghrelin in obesity and endocrine diseases

“…Co-segregation was seen for all obese individuals in the Czech pedigree; however two members of this pedigree were carriers of this mutation but not obese, possibly due to incomplete penetrance. The -151C/T mutation was subsequently genotyped in a population-based study of 15,854 Danish subjects; however in this study no association was found between the -151C/T mutation and obesity (Gjesing et al, 2010). …”

“…In addition, a A c c e p t e d M a n u s c r i p t 14 population-based study of 15,854 Danish subjects, in which seven common GHS-R SNPs were genotyped, failed to show association between the GHS-R variants and obesity (Gjesing et al, 2010). Further clinical studies are required to better define the frequency and the aetiological role of GHS-R isoforms in obesity ).…”

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

“…Although ghrelin is an orexigenic hormone primarily synthesized by X/A cells of the gastric mucosa, various attempts to relate genetic alterations of either ghrelin (5,6) or the GHSR (5,12,13,14,15) to body weight have yielded inconsistent results. Baessler et al (12) found that a disequilibrium block of five GHSR SNPs including rs572169 was associated with obesity.…”

“…Several large studies in various populations have investigated the effects of common GHSR variants on stature, weight, and body mass index (BMI) (4,5,12,13,14,15). Baessler et al (12) reported an association between GHSR variants and obesity; however, other studies have yielded negative results (5,13,14,15).…”

“…Baessler et al (12) reported an association between GHSR variants and obesity; however, other studies have yielded negative results (5,13,14,15).…”