Polymorphisms in the leptin and leptin receptor genes, cardiometabolic health, and eating behavior in women with systemic lupus erythematosus

• Grant number: 24/03408-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2025
• End date: March 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Carolina Nicoletti Ferreira Fino
• Grantee: Jhulia Caroline Nunes Leal da Mota
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with mechanisms associated with an increased predisposition to developing cardiometabolic disorders. The systemic inflammation characteristic of SLE, along with autoantibody production, medication effects, and an inadequate lifestyle, are some factors that explain this relationship. Leptin acts through its membrane receptor and is closely connected to this scenario. Given its established effects on energy metabolism, leptin plays a key role in controlling food intake, eating behavior, and cardiometabolic health. Both the gene encoding human leptin (LEP) and the gene encoding the leptin receptor (LEPR) appear to be associated with the development of obesity, type 2 diabetes mellitus (T2DM), and cardiometabolic risk. Since the mechanism of leptin in the pathogenesis of SLE and the role of genetic variants in leptin-related metabolism genes in the metabolic health and eating behavior of SLE patients remain unknown, this study aims to assess the potential influence of single nucleotide polymorphisms (SNPs) in the LEP and LEPR genes on leptin expression and function, examining the possible impact of these SNPs on the leptin signaling pathway, cardiometabolic health, and eating behavior disorders in women with SLE. Initially, a cross-sectional case-control study will be conducted with patients with and without an SLE diagnosis. Patients will be recruited for the SLE group (N = 200) according to pre-established inclusion criteria: (1) female sex; (2) pre-menopausal period; (3) between 18 and 45 years of age; (4) classified according to the Systemic Lupus International Collaborating Clinics (SLICC) criteria; (5) disease in remission; (6) prednisone treatment at a dosage <10 mg/day; and (7) hydroxychloroquine treatment at a stable dose. For the CONTROL group (N = 100), healthy women aged 18 to 45, in the pre-menopausal period, without any ongoing inflammatory disease, and not using glucocorticoids, will be recruited. Both groups will undergo fasting blood collection (for genetic, biochemical, and inflammatory analyses), blood pressure evaluation, body composition assessment, food intake and eating behavior assessment, and physical activity evaluation. Genetic analyses will include genotyping of LEP SNPs (G2548A; G19A) and LEPR SNPs (K109R; Q223R), as well as the expression of LEP and LEPR genes in peripheral blood mononuclear cells (PBMCs), both by real-time Polymerase Chain Reaction (PCR). If this study identifies significant associations between risk alleles and phenotypic characteristics, a second experimental study will assess the biological plausibility of these associations. Thus, an in vitro assay will be conducted using PBMCs from participants with and without the risk allele. The cells will be cultured in culture medium and treated with recombinant leptin for 48 hours. After this period, the expression of Janus kinase 2 (JAK2), phosphorylated JAK2, signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3, and phosphorylated LEPR proteins will be evaluated. Statistical analyses will include the Komolgorov-Smirnov test, Chi-square test (¿2), t-test for independent samples, and the Mann-Whitney test. To assess the magnitude of the association between the studied polymorphisms and cardiometabolic health, crude and adjusted odds ratios (OR) with their respective 95% confidence intervals (CIs) will be estimated. Additionally, regression models will be used to evaluate the potential effect of alleles on secondary variables. These analyses will be adjusted for possible confounders such as age, ethnicity, socioeconomic level, educational level, BMI, and current medications. The significance level adopted will be p¿0.05.