Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity

Giudice, Emanuele Miraglia del; Santoro, Nicola; Cirillo, Grazia; Raimondo, Paolo; Grandone, Anna; D’Aniello, A.; Nardo, Michele Di; Perrone, Laura

doi:10.1038/sj.ijo.0802572

Cited by 85 publications

(44 citation statements)

References 23 publications

(18 reference statements)

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“…Additionally, obese Italian children and adolescents with the preproghrelin 72Met allele have also been reported to become obese earlier than homozygous patients for the wild Leu72 allele, even though 72Met allelic frequency was similar between obese and control groups. 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.…”

Section: Discussionmentioning

confidence: 86%

“…5,6 Recently, three major polymorphisms in the human ghrelin gene were described. 7 One of these nucleotide changes, a single-base substitution C214A with Met replacing Leu at codon 72 in the preproghrelin amino-acid sequence, seems to be associated with an earlier onset of obesity, [7][8][9] but it has also been proposed that 72Met could provide protection against the accumulation of fat. 10 Thus, previous studies on preproghrelin genetic variants have arrived at contradictory findings as to their role in obesity.…”

Section: Introductionmentioning

confidence: 99%

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

Kuzuya

Ando²,

Iguchi

et al. 2006

Int J Obes

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Objective: To investigate whether Leu72Met polymorphism of the preproghrelin gene is associated with overweight/obesity in middle-aged and older Japanese. Design: Cross-sectional analysis. Subjects: A total of 2238 community-dwelling middle-aged and older Japanese people (age: 40-79 years) who participated in the first wave of examinations in the National Institute for Longevity Sciences -Longitudinal Study of Aging from April 1998 to March 2000. Measurements: The Leu72Met polymorphism of prepoghrelin gene, anthropometric variables including body weight, body mass index (BMI), waist circumference, waist-to-hip ratio and whole-fat mass and biochemical variables including serum lipid levels, fasting plasma glucose, insulin and homeostasis model assessment for insulin resistance. Results: The frequencies of the Leu72Leu, Leu72Met and Met72Met alleles were 63.4, 32.7 and 4.0%, respectively. No differences in the genotype distributions of the Leu72Met polymorphism were found between genders or age groups, and no significant associations were observed between polymorphism and anthropometric variables in women and older men. However, middle-aged men who were 72Met allele carriers showed a higher body weight change from body weight at 18 years of age, as well as a higher waist circumference and a tendency to a higher waist-hip-ratio than noncarriers. Although there were no significant differences in the genotype distribution according to BMI in women and older men, a significantly higher frequency of the 72Met allele was found in the higher BMI group (BMIX25 kg/m 2 ) of middle-aged men than in the normalweight group. No significant associations were observed between polymorphism and serum lipid, glucose or insulin levels. Conclusions: These results suggest that the 72Met allele of the preproghrelin gene is a contributing factor for midlife weight change in men.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

Kuzuya

Ando²,

Iguchi

et al. 2006

Int J Obes

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“…12 Obestatin reduces food intake and slows bowel motility, but has no effect on growth hormone release. Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion; [13][14][15][16] Met72 allele carriers of Leu72Met variant seem to be protected against fat accumulation and visceral metabolic disorders. It has been shown as an association of such variants with type 2 diabetes-related phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…15,17 However, with regard to the association between polymorphisms in GHRL and obesity-related metabolic disorders, published reports are conflicting. [13][14][15][16][17] In view of these considerations, we evaluated the possible association of the three GHRL haplotype-tagging single nucleotide polymorphisms (SNPs) À604 C4T, Leu72Met and Gln90Leu, with obesity and metabolic abnormalities of the insulin resistance state in a large population of individuals. The first polymorphism is a variation located in the promoter region of GHRL gene; the Leu72Met (C247A) is located between the mature ghrelin and the obestatin peptide.…”

Section: Introductionmentioning

confidence: 99%

A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance

et al. 2007

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Objective: Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion. We evaluated the association of a new variation, À604C4T, in the promoter region of the ghrelin gene, of Leu72Met (247C4A) and of Gln90Leu (265A4T), all haplotypetagging single nucleotide polymorphisms (SNPs), with measures of insulin sensitivity in 1420 adult individuals. Research methods: The three SNPs were genotyped using ABI PRISM 7900 HT Sequence Detection System. We used multiple linear regression analysis for quantitative traits and THESIAS software for haplotype analysis. Results: We observed a protective effect exerted by Met72 variant of Leu72Met SNP on insulin resistance parameters; a significant decreasing trend from Leu/Leu to Leu/Met and to Met/Met homozygous subjects in triglycerides, fasting insulin levels and HOMA-IR index (P ¼ 0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P ¼ 0.003) was found. A significant decrease from CC to TC and to TT genotypes in insulin levels and HOMA-IR index was also detected (P ¼ 0.00l for both), but only in subjects homozygous for Leu72, where the protective effect of Met72 was not present. The haplotype analysis results supported the data obtained by the evaluation of each single SNP, showing the highest value of insulin levels and HOMA-IR index in the À604 T 247 C and lowest value in À604 C 247 A . Conclusion: Our observations suggest a protective role of the Met72 variant and of À604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.

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“…This SNP results in an amino acid substitution (leucine to methionine) at residue 72 which is outside the mature ghrelin product of 28 amino acids. Although its function is yet to be established, this polymorphism has been associated with several medical and psychiatric conditions, including diabetes (Liao et al, 2013), development of obesity (Miraglia del Giudice et al, 2004) and depression (Nakashima et al, 2008). However, its potential involvement in alcohol use disorders (AUD) is less clear.…”

Section: Introductionmentioning

confidence: 99%

The Leu72Met Polymorphism of the Prepro-ghrelin Gene is Associated With Alcohol Consumption and Subjective Responses to Alcohol: Preliminary Findings

Suchankova

Yan

Schwandt

et al. 2017

Alcohol and Alcoholism

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Aims: The orexigenic peptide ghrelin may enhance the incentive value of food-, drug-and alcoholrelated rewards. Consistent with preclinical findings, human studies indicate a role of ghrelin in alcohol use disorders (AUD). In the present study an a priori hypothesis-driven analysis was conducted to investigate whether a Leu72Met missense polymorphism (rs696217) in the prepro-ghrelin gene (GHRL), is associated with AUD, alcohol consumption and subjective responses to alcohol. Method: Association analysis was performed using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) clinical sample, comprising AUD individuals and controls (N = 1127). Then, a post-hoc analysis using data from a human laboratory study of intravenous alcohol selfadministration (IV-ASA, N = 144) was performed to investigate the association of this SNP with subjective responses following a fixed dose of alcohol (priming phase) and alcohol selfadministration (ad libitum phase). Results: The case-control study revealed a trend association (N = 1127, OR = 0.665, CI = 0.44-1.01, P = 0.056) between AUD diagnosis and Leu72Met. In AUD subjects, the SNP was associated with significantly lower average drinks per day (n = 567, β = −2.49, 95% CI = −4.34 to −0.64, P = 0.008) and significantly fewer heavy drinking days (n = 567, β = −12.00, 95% CI = −19.10 to −4.89, P < 0.001). The IV-ASA study further revealed that 72Met carriers had greater subjective responses to alcohol (P < 0.05) when compared to Leu72Leu both at priming and during ad lib selfadministration.

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Molecular screening of the ghrelin gene in Italian obese children: the Leu72Met variant is associated with an earlier onset of obesity

Cited by 85 publications

References 23 publications

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

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

A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance

The Leu72Met Polymorphism of the Prepro-ghrelin Gene is Associated With Alcohol Consumption and Subjective Responses to Alcohol: Preliminary Findings

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