The agouti-related protein and body fatness in humans

Abstract

OBJECTIVE:The objective of this study was to examine the impact of a single nucleotide polymorphism (SNP) (À38C>T) in the promoter of the human agouti-related protein (hAgRP) gene on promoter affinity for transcription factors (TFs) and its possible association with body composition phenotypes. DESIGN: Electrophoretic mobility shift assays for the functional studies and association analyses for the population studies. SUBJECTS AND METHODS: Nuclear extracts were isolated from the mouse hypothalamus cell line GT1-7 and subjected to binding assays using oligonucleotide probes corresponding to the À38C>T region and an antibody for the E12/E47 TFs. Individuals (n = 259) from the HERITAGE Family Study were genotyped for the À38C>T SNP and used in the association studies. RESULTS: Electrophoretic mobility shift and supershift assays confirmed binding of the E12/E47 TF to the À38C>T site in a genotype-dependent manner. The T allele was found exclusively in the black subjects while the genotype with the higher binding affinity, CC, was significantly associated with high BMI, fat mass, and percent body fat in the black subjects of the HERITAGE Family Study. CONCLUSIONS: The E12/E47 TF could play a role in the regulation of hAgRP expression while the population studies suggest that the TT genotype of the À38C>T SNP could play a protective role against the development of obesity in the black population of the HERITAGE Family Study.

Early growth response protein 1 acts as an activator of SOX18 promoter

“…Both competition with EGR1 consensus probe and addition of anti-EGR1 antibody caused fading of DNA-protein complexes ( Figure 3B, lanes 21 and 22, respectively). Fading of DNA-protein complexes in supershift reaction has already been shown in several reports and was considered as a confirmation of specific protein presence (Argyropoulos et al, 2003;Kovacevic Grujicic et al, 2005). In order to further validate obtained results, we have per- Figure 4.…”

African Genetic Diversity: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping

“…For example, polymorphisms in the promoter of the angiotensin-converting enzyme (ACE) gene are correlated with obesity in Nigerians and African Americans (105). Also, allelic variation in the promoter of the agouti-related protein (AGRP) gene was found to affect gene expression and was implicated in the regulation of body weight in people of African origin (11,22).…”

A rare mutation in AgRP, +79G>A, affects promoter activity

“…SNP À3019G4A was in complete linkage disequilibrium with SNP À38C4T, but the two linked alleles had opposite effects on promoter activity with the net effect likely being determined by the À38C4T SNP because of its position in a region with 1000-fold higher promoter activity . The T allele of the À38C4T SNP has been associated with leanness in Sierra Leonean black subjects and reduced fatness in black subjects of the HERITAGE Family Study (Argyropoulos et al, 2003). In addition, the T/T genotype was associated with resistance to developing type 2 diabetes mellitus in Sierra Leoneans ) a finding that was confirmed by an independent study in a different cohort of West Africans (Bonilla et al, 2006).…”

“…Mutation screening of the minimal promoter of AgRP and genotyping were carried out as described previously (Sozen et al, 2001;Argyropoulos et al, 2003). A cohort of 95 individuals comprising blacks (N ¼ 47) and whites (N ¼ 48) was screened for the presence of mutations in AgRP.…”