Leu72Met polymorphism of GHRL gene decreases susceptibility to type 2 diabetes mellitus in a Mexican population

Abstract

Background: Type 2 diabetes mellitus (T2D) is the most frequent type of diabetes. It has a multifactorial etiology, affecting millions of people worldwide. Ghrelin gene (GHRL) encodes the ghrelin peptide, which promotes food intake, induces body weight and adipogenesis. Several single nucleotide polymorphisms (SNPs) in GHRL gene have been associated with metabolic diseases. A protective effect of the Leu72Met (rs696217) polymorphism has been described for T2D in some populations, but this effect seems to depend on the ethnicity of the patients studied. Methods: The aim of this study was to investigate the association between the GHRL Leu72Met (rs696217) SNP with the development of T2D and serum ghrelin levels in a Western Mexican population. We performed a casecontrol study in which we included 284 subjects (159 with previous T2D diagnosis and 125 control subjects (CS)). Leu72Met SNP was genotyped by using PCR-RFLPs technique. Serum ghrelin levels were measured using a commercial enzyme immunoassay. Genotypic and allelic distributions were compared using Chi square test. Student T-test and Mann-Whitney U test were used to compare quantitative variables. Odds ratio (OR) was used to evaluate the association between alleles or genotypes and T2D. Multiple and logistic regression models were performed for adjustment. A two-tailed p-value ≤0.05 was considered statistically significant. Results: Leu72Leu genotype was more frequent among T2D compared to CS (p < 0.05). After adjusting for age and body composition, there was a significant protective effect of the 72Met allele for T2D development (OR 0.40 IC 95% 0.23-0.70; p ≤ 0.001). Fasting serum ghrelin levels were lower in T2D than CS (p ≤ 0.0001) irrespective of age, body weight and BMI. No associations were found between genotypes and ghrelin serum levels in our population. Conclusions: The GHRL 72Met allele decreases susceptibility for T2D development in a Western Mexican population. Serum ghrelin levels are lower in T2D independently of Leu72Met polymorphism genotype.

Whole Exome Sequencing Reveals Rare Variants in Genes Associated with Metabolic Disorders in Women with PCOS

“…[ 51 52 ] The association of GHRL p.Leu72Met with insulin resistance and T2DM risk has remained controversial. [ 53 54 55 ] However, a positive association between GHRL p.Leu72Met and early onset of obesity was found amongst Italian obese children. [ 56 ] In our cohort, we have identified GHRL p.Leu72Met in five PCOS patients, of which three were obese and two subjects had normal BMI.…”

Role of Leu72Met of GHRL and Gln223Arg of LEPR Variants on Food Intake, Subjective Appetite, and Hunger-Satiety Hormones

“…The genotypic and allelic frequencies of the genotypes of GHRL Leu72Met in our study were similar to those reported in a Mexican-American population of Los Angeles [ 33 ]. Nevertheless, Rivera-León et al observed different frequencies in a population of young adults from western Mexico with both normal weight and obesity; a possible explanation for this might be the use of different techniques to determine the genotypes [ 34 ]. Moreover, the allelic and genotypic frequencies of Gln223Arg genotypes of the LEPR gene were similar to those reported in the Mexican-American population of Los Angeles [ 35 ], as well as in young populations with normal weight and overweight in southern and western Mexico [ 34 , 35 , 36 ].…”

Analysis of rare coding variants in 200,000 exome‐sequenced subjects reveals novel genetic risk factors for type 2 diabetes

“…Damaging variants in GYG1 (SLP = 3.22) cause deficiency of glycogenin 1, resulting in glycogen storage myopathies, but have not been reported to be associated with diabetes 33 . GHRL (SLP = −3.15) encodes the ghrelin‐obestatin preproprotein which is cleaved to yield two peptides, ghrelin and obestatin, which are involved in appetite and energy metabolism and there have been some studies which have claimed that the common Leu72Met (rs696217) variant is associated with reduced risk of T2D although the effect does not seem to be consistent and the gene was not highlighted in a large GWAS meta‐analysis 1,34 …”

“…33 GHRL (SLP = −3.15) encodes the ghrelin-obestatin preproprotein which is cleaved to yield two peptides, ghrelin and obestatin, which are involved in appetite and energy metabolism and there have been some studies which have claimed that the common Leu72Met (rs696217) variant is associated with reduced risk of T2D although the effect does not seem to be consistent and the gene was not highlighted in a large GWAS meta-analysis. 1,34 It is noteworthy that in the gene set analyses the second high- 12 of 14 -CURTIS function effects. 38 The fact that the frequency of LOF variants in INSR is similar in cases and controls, indicates that, although recessively acting variants can cause infantile hyperinsulinaemia followed by insulin dependent diabetes, the loss of function of a single copy of this gene has little discernible effect on risk of T2D.…”