Molecular dynamic (MD) studies on Gln233Arg (rs1137101) polymorphism of leptin receptor gene and associated variations in the anthropometric and metabolic profiles of Saudi women

Daghestani, Maha H.; Purohit, Rituraj; Daghestani, Mazin H.; Daghistani, Mamoon; Warsy, Arjumand S.

doi:10.1371/journal.pone.0211381

Cited by 23 publications

(22 citation statements)

References 49 publications

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“…Evidence suggests that the resulting conformational changes of the protein influence the LEPR functions and could lead to an abnormal downstream signaling pathway of JAK2 due to a leptin receptor deficiency. The consequences of these abnormalities are leptin resistance and, therefore, an attenuated leptin signaling [23]. Accordingly, it would result in a more significant presence of obesity by Q223R genotype, as we have seen in this study, as well as in previous researches in both pediatric [24,25] and adulthood populations [26][27][28].…”

Section: Discussionsupporting

confidence: 72%

The Q223R Polymorphism of the Leptin Receptor Gene as a Predictor of Weight Gain in Childhood Obesity and the Identification of Possible Factors Involved

Marcos-Pasero

Aguilar-Aguilar

Colmenarejo

et al. 2020

Genes

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(1) Background: Childhood rapid weight gain during development has been postulated as a predictor of obesity. The objective of this study was to investigate the effect of single nucleotide polymorphisms (SNPs) on the annual weight gain and height growth, as well as identifying possible lifestyle factors involved. (2) Methods: As part of the GENYAL study, 221 children (6–8 years old) of Madrid (Spain) were enrolled. A total of 11 SNPs associated with high childhood body mass indexes (BMIs) were assessed. Anthropometric measurements, dietary and physical activity data, were collected in 2017 and 2018. Bonferroni-corrected linear models were used to fit the data. (3) Results: A significant association between the Q223R LEPR and the weight growth was found, showing a different behavior between GA and GG genotypes (p = 0.001). Regarding lifestyle factors, an interaction between Q223R genotypes and total active weekly hours/week to predict the weight growth (kg/year) was observed (p = 0.023). In all the genotypes, a beneficial effect against rapid weight growth was observed, but the effect size of the interaction was much more significant in homozygous (GG) minor homozygous (β = −0.61 (−0.95, −0.26) versus heterozygous (AG) and wild-type homozygous (AA) genotypes (β = −0.07 (−0.24, 0.09) and β = −0.12 (−0.32, 0.08), respectively). (4) Conclusions: These results may contribute to more personalized recommendations to prevent childhood obesity.

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Section: Discussionsupporting

confidence: 72%

The Q223R Polymorphism of the Leptin Receptor Gene as a Predictor of Weight Gain in Childhood Obesity and the Identification of Possible Factors Involved

Marcos-Pasero

Aguilar-Aguilar

Colmenarejo

et al. 2020

Genes

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“…Authors argue that the cause of obesity is not the defects in leptin, but that the problem lies in the resistance to leptin. Leptin resistance can occur due to defects in the gene itself (polymorphism, lipoprotection, voltage of the endoplasmic reticulum), as well as post receptor defect in hormone action (inflammatory reactions), which may interfere with intracellular transport of messages (Lopez et al, 2016;Daghestani et al, 2019). In this study we also have proved that in pregnant women with LEPR Gln223Arg gene GG-polymorphism, excessive serum hyperleptinemia is based on leptin resistance due to modified transcriptional activity of the LEPR gene.…”

Section: Discussionmentioning

confidence: 53%

Genetic aspects of metabolic disorders in pregnant women with pathological weight gain

Ostafiichuk

2019

Regul. Mech. Biosyst.

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Polymorphism of the leptin receptor gene (LEPR) has been shown to be linked to obesity-related metabolic markers and phenotype. Therefore, we hypothesized that the Gln233Arg LEPR polymorphism is related to metabolic changes in pregnancy and the risk of excessive gestational weight gain (GWG). A total of 97 pregnant women with a singleton gestation were enrolled from April 2016 until December 2018. Genetic variants of LEPR were analyzed by real-time polymerase chain reaction, leptin by enzyme-linked immunosorbent assay, lipid profile, and carbohydrate status were assessed in the first, and third trimesters of pregnancy. The recommended GWG was diagnosed in 34.0%, insufficient in 19.6%, and excessive in 46.4% patients. Statistical analysis revealed that 20.6% patients were with AA genotype, 50.5% – AG genotype, and 28.9% – GG genotype. The frequency of GG-alleles carriers of the LEPR Gln233Arg gene in the group of excessive GWG patients was 3 times higher compared to recommended GWG patients. Thus, the inheritance of pathological G-homozygotes increases the risk of excessive weight gain by 7 times, compared to carriers of the AA genotype. LEPR GG polymorphism was significantly associated with high levels of triglycerides, total cholesterol, lipoprotein low and very low density, and leptin compared to homozygous А-carriers in the third trimester of pregnancy. In pregnant women with GG polymorphism, the glucose level, insulin level, and HOMO-IR index were significantly increased compared to women with AA genotype in late pregnancy. In the group with excessive GWG, the presence of GG-alleles of the LEPR gene was accompanied by a higher level of hyperleptinemia, compared to carriers of AA-genotype. Inheritance of pathological G-homozygotes was associated with hyperlipidemia, leptin resistance with high leptin serum levels, and increased insulin resistance, which was especially manifested in excessive GWG. In our opinion, excessive GWG can be seen as a marker of the mother's genotype and genetic predisposition to the development of metabolic diseases after delivery.

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“…However, when we carried out, in our Mediterranean population, a whole gene screening to capture a more complete set of SNPs in the same candidate genes (LEP, SLC32A, GCKR, CCNL1, COBLL1, and FTO), we did obtain several statistically significant association between other SNPs in these genes and plasma leptin concentrations. In addition to those genes, we included the LEPR gene that, although not showing up as relevant in the GWAS de Kilpeläin et al [37], has been reported in other studies as having significant associations of SNPs in the LEPR gene with circulating leptin levels [24,26,33,74]. In the LEPR screening, we also found several SNPs showing statistically significant associations with leptin levels in our population.…”

Section: Discussionmentioning

confidence: 76%

Candidate Gene and Genome-Wide Association Studies for Circulating Leptin Levels Reveal Population and Sex-Specific Associations in High Cardiovascular Risk Mediterranean Subjects

et al. 2019

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Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p < 1 × 10−5 level, among them with the rs245908-CHN2 SNP (p = 1.6 × 10−6). We also detected a SNP*sex interaction at the GWAS significance level (p < 5 × 10−8), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.

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Molecular dynamic (MD) studies on Gln233Arg (rs1137101) polymorphism of leptin receptor gene and associated variations in the anthropometric and metabolic profiles of Saudi women

Cited by 23 publications

References 49 publications

The Q223R Polymorphism of the Leptin Receptor Gene as a Predictor of Weight Gain in Childhood Obesity and the Identification of Possible Factors Involved

The Q223R Polymorphism of the Leptin Receptor Gene as a Predictor of Weight Gain in Childhood Obesity and the Identification of Possible Factors Involved

Genetic aspects of metabolic disorders in pregnant women with pathological weight gain

Candidate Gene and Genome-Wide Association Studies for Circulating Leptin Levels Reveal Population and Sex-Specific Associations in High Cardiovascular Risk Mediterranean Subjects

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