Association of the G/G Genotype with Insulin Resistance, Dyslipidemia, And Hyperleptinemia

Abstract

Background. Obesity is a multifactorial disease arising from interactions among environmental, behavioural, metabolic, and genetic factors. The leptin signalling system is a key component of the central regulation of energy balance. The rs1137100 polymorphism of the leptin receptor gene (LEPR) results in the Lys109Arg amino acid substitution and may be associated with variability in leptin sensitivity and the metabolic characteristics of obesity. However, findings vary considerably across populations.

Objective. To evaluate the distribution of alleles and genotypes of the LEPR rs1137100 polymorphism in patients with overweight and obesity and to determine the associations between these genotypes and lipid metabolism, insulin resistance, and circulating leptin levels.

Materials and Methods. The clinical cohort included 171 patients with overweight or obesity. Molecular genetic testing was performed in 74 patients (67 women and 7 men; mean age, 38.5 ± 1.4 years; mean body mass index [BMI], 37.7 ± 0.8 kg/m²). The control group consisted of 70 apparently healthy individuals with normal body weight (mean BMI, 22.6 ± 0.6 kg/m²). Genomic DNA was isolated from peripheral blood leukocytes using the NK-Magnit Base-96 kit. The rs1137100 polymorphism was genotyped using polymerase chain reaction followed by restriction fragment analysis. The A and G alleles and the A/A, A/G, and G/G genotypes were identified. The metabolic phenotype was assessed based on total cholesterol, low-density lipoprotein cholesterol, triglyceride and leptin concentrations, as well as the homeostatic model assessment of insulin resistance (HOMA-IR). Statistical analyses were performed using STATISTICA version 10.0 and Epi Info version 7.2.2.2.

Results. The G/G genotype was identified in 32.4% of patients and 12.9% of controls (OR = 3.25; 95% CI, 1.42–7.44; p = 0.006, Fisher’s exact test). The frequency of the G/G genotype was 30.8% among patients with overweight or class I–II obesity and 36.4% among those with class III obesity; however, direct comparison according to obesity severity revealed no statistically significant differences. Within the patient group, the metabolic parameters progressively worsened across the A/A, A/G, and G/G genotypes. Compared with A/A carriers, G/G carriers had higher levels of low-density lipoprotein cholesterol (3.71 ± 0.05 vs 3.03 ± 0.04 mmol/L), triglycerides (2.23 ± 0.03 vs 1.64 ± 0.03 mmol/L), total cholesterol (5.81 ± 0.06 vs 4.95 ± 0.08 mmol/L), HOMA-IR (4.34 ± 0.04 vs 2.81 ± 0.05), and leptin (29.87 ± 0.80 vs 21.30 ± 0.90 ng/mL).

Conclusion. In the study population, the G/G genotype of the LEPR rs1137100 polymorphism was associated with obesity and a more adverse metabolic phenotype. However, this genotype did not independently differentiate between obesity severity categories. These findings suggest that the G/G genotype may be considered a candidate marker of a metabolically adverse obesity phenotype, although confirmation in larger independent cohorts and multivariable models is required.

Keywords:

Obesity, LEPR, rs1137100, K109R

References

Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol. 2019;15(5):288–298. doi:10.1038/s41574-019-0176-8.

World Health Organization. Obesity and overweight: fact sheet [Internet]. Geneva: World Health Organization; 2024 [cited 2026 Sep 13]. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

Lingvay I, Cohen RV, le Roux CW, Sumithran P. Obesity in adults. Lancet. 2024;404(10456):972–987. doi:10.1016/S0140-6736(24)01210-8.

Loos RJF, Yeo GSH. The genetics of obesity: from discovery to biology. Nat Rev Genet. 2022;23(2):120–133. doi:10.1038/s41576-021-00414-z.

Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab. 2019;1(8):754–764. doi:10.1038/s42255-019-0095-y.

Pan WW, Myers MG Jr. Leptin and the maintenance of elevated body weight. Nat Rev Neurosci. 2018;19(2):95–105. doi:10.1038/nrn.2017.168.

Wauman J, Zabeau L, Tavernier J. The leptin receptor complex: heavier than expected? Front Endocrinol (Lausanne). 2017;8:30. doi:10.3389/fendo.2017.00030.

Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, obesity, and leptin resistance: where are we 25 years later? Nutrients. 2019;11(11):2704. doi:10.3390/nu11112704.

Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, et al. Leptin and obesity: role and clinical implication. Front Endocrinol (Lausanne). 2021;12:585887. doi:10.3389/fendo.2021.585887.

Gupta A, Gupta P, Singh AK, Gupta V. Association of adipokines with insulin resistance and metabolic syndrome including obesity and diabetes. GHM Open. 2023;3(1):7–19. doi:10.35772/ghmo.2023.01004.

National Center for Biotechnology Information. LEPR leptin receptor [Homo sapiens (human)]. Gene ID: 3953 [Internet]. Bethesda (MD): National Library of Medicine [cited 2026 Sep 13]. Available from: https://www.ncbi.nlm.nih.gov/gene/3953.

Kochetova OV, Avzaletdinova DS, Sharipova LF, Korytina GF, Akhmadishina LZ, Morugova TV, et al. An analysis of the associations of polymorphic variants of the LEPR, LRP5, and LPL genes with the risk of developing type 2 diabetes mellitus. Russ J Genet. 2019;55(4):495–503. doi:10.1134/S1022795419040057.

Almyah MK, Al-Awadi SJ, Al-Derzi AR, et al. Genetic susceptibility of Iraqis for obesity and type 2 diabetes: LEPR gene polymorphisms. Gene Rep. 2019;15:100386. doi:10.1016/j.genrep.2019.100386.

Jarrar M, et al. Association of LEP rs2167270 and LEPR rs1137100 genetic variants with obesity in the Jordanian population cohort. F1000Research. 2024;13:620. doi:10.12688/f1000research.142344.1.

Prodan A, Dzubanovsky I, Kamyshnyi O, et al. GHRL, LEP, LEPR genes polymorphism and their association with the metabolic syndrome in the Ukrainian population. Endocr Regul. 2023;57(1):269–278. doi:10.2478/enr-2023-0039.

Cha YJ, et al. Association between LEPR genotype and gut microbiome in healthy non-obese Korean adults. Biomol Ther (Seoul). 2024;32(1):146–153. doi:10.4062/biomolther.2023.116

Ievleva KD, Bairova TA, Sheneman EA, Ayurova ZG, Balzhieva VV, Novikova EA, et al. The effect of polymorphisms of energy metabolism genes on metabolic disorders in overweight adolescents of two ethnicities. Bull Exp Biol Med. 2022;172(4):430–434. doi:10.1007/s10517-022-05408-3.

El Fessikh M, Elkarhat Z, Flatters D, Camproux AC, Belghiti H, Guerinech H, et al. Association study of leptin receptor polymorphisms in women with obesity and their impact on protein domains: a case-control study and in silico analyses. J Biomol Struct Dyn. 2023;41(14):6546–6558. doi:10.1080/07391102.2022.2109755.

19.Penes ON, Bodnarescu-Cobanoglu MN, et al. Gene polymorphisms LEP, LEPR, 5HT2A, GHRL, NPY, and FTO—obesity biomarkers in metabolic risk assessment: a retrospective pilot study in overweight and obese patients. Genes (Basel). 2024;15(7):860. doi:10.3390/genes15070860.

Shagazatova B.X., Artikova D.M., Islamova J.I. Evolutionary Development and Functional State of the Hypothalamic-Pituitary System (Literature Review) // Central Asian Journal of Medicine. – 2024. – No. 4. – P. 239–250.