Ghrelin Gene: Identification of Missense Variants and a Frameshift Mutation in Extremely Obese Children and Adolescents and Healthy Normal Weight Students

Abstract

Ghrelin induces obesity via central and peripheral mechanisms. Administration of ghrelin leads to increased food intake and decreased fat utilisation in rodents. Ghrelin levels are decreased in obese individuals. Recently, a polymorphism (Arg-51-Gln) within the ghrelin gene (GHRL) was described to be associated with obesity. We screened the GHRL coding region in 215 extremely obese German Children and adolescents (study group 1) and 93 normal weight students (study group 2) by single strand conformation polymorphism analysis (SSCP). We found the two previously described single nucleotide polymorphisms (SNP: Arg-51-Gln and Leu-72-Met) in similar frequencies in study groups 1 and 2 (allele frequencies were: 0.019 and 0.016 for the 51-Gln allele and 0.091 and 0.086 for the 72-Met allele, respectively). Hence, we could not confirm the previous finding. Additionally, two novel variants were identified within the coding region: (1) We detected one healthy normal weight individual with a frameshift mutation (2bp deletion at codon 34). This frameshift mutation affects the coding region of the mature ghrelin. Hence, it is highly likely that the normal weight student is haplo-insufficient for ghrelin. (2) An A to T transversion leads to an amino acid exchange from Gln to Leu at amino acid position 90. The frequency of the 90-Leu allele was significantly higher in the extremely obese children and adolescents (0.063) than in the normal weight students (0.016; nominal p = 0.011). Additionally, we genotyped 134 underweight students and 44 normal weight adults for this SNP. Genotype frequencies were similar in extremely obese children and adolescents, underweight students and normal weight adults (p > 0.8). In conclusion, we identified four sequence variants in the coding region of the ghrelin gene in individuals belonging to different weight extremes. A frameshift mutation was detected in a normal weight individual. None of the variants seem to influence weight regulation.

Ghrelin in obesity and endocrine diseases

“…In addition, the Leu72Met polymorphism has been suggested to contribute to weight gain in middle-aged Japanese men (Kuzuya et al, 2006). However, the above findings could not be reproduced by other studies (Bing et al, 2005;Hinney et al, 2002;Jo et al, 2005;Zhu et al, 2010). Furthermore, one study of 3004 subjects even reported the Leu72Met polymorphism to be protective against fat accumulation; the polymorphism was related to lower BMI, fat mass and reduced visceral fat (Ukkola et al, 2002).…”

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

“…Noticeably, the european study found an association between the Leu90OBE polymorphism and AN in the german population whose control group showed a lower frequency of the Gln/Leu genotype compared to the combined spanish and italian controls (1.2 % versus more than 7 % for the other groups, (Cellini et al, 2006)). This low allele frequency in the control group was previously reported in a german study showing an association between this polymorphism and obesity but considered as a false positive association because a second control group of underweight students had the same Leu90OBE allele frequency (Hinney et al, 2002).…”

Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort

“…8 These findings were not confirmed, however, in a group of extremely obese German children. 14 In addition, one report P-value by the w 2 analysis among groups CC, CA and AA. P*-value by the w 2 analysis between groups CC and CA/AA.…”