Association Studies on Ghrelin and Ghrelin Receptor Gene Polymorphisms With Obesity

Abstract

Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.

Ghrelin in obesity and endocrine diseases

“…Relationships have been described between obesity and genomic variants of the ghrelin (GHRL) (Gueorguiev et al, 2009;Korbonits et al, 2002;Kuzuya et al, 2006;Leskela et al, 2009;Miraglia Del et al, 2004;Ukkola et al, 2001;Ukkola et al, 2002) M a n u s c r i p t 12 and ghrelin receptor (GHS-R) (Baessler et al, 2005;Gueorguiev et al, 2009;Liu et al, 2007) genes.…”

“…Direct sequencing identified 12 GHRL single-nucleotide polymorphisms (SNPs) and 8 GHS-R SNPs (Gueorguiev et al, 2009). The GHRL polymorphism A265T and the GHS-R polmorphism G477A have been associated with obesity in a French cohort of 263 families, while the GHRL variant Leu72Met (C247A) and GHS-R variant C60T may modulate eating patterns.…”

“…The GHRL polymorphism A265T and the GHS-R polmorphism G477A have been associated with obesity in a French cohort of 263 families, while the GHRL variant Leu72Met (C247A) and GHS-R variant C60T may modulate eating patterns. However, after correction for multiple comparisons and testing in a German cohort with early-onset extreme obesity, it appears that these variants of GHRL and GHS-R genes are not strong genetic factors determining the susceptibility to obesity (Gueorguiev et al, 2009). for the involvement of the GHS-R gene in body weight regulation (Wang et al, 2004).…”

GH secretagogue receptor gene polymorphisms are associated with stature throughout childhood

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

“…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).…”