Associação de variantes genéticas em LXRA e LXRB com fenótipos de Esclerose Lateral Amiotrófica

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a chronic, fatal neurodegenerative disease that affects motor neurons and leads to premature death. In most cases, its etiology remains unknown. The LXRA and LXRB genes encode the LXR-alpha and LXR-beta proteins, respectively. These nuclear receptors function as key transcription factors involved in lipid metabolism and exert neuroprotective and anti-inflammatory effects in the central nervous system. Objective: This study investigated the association between the genetic variants rs2279238 (LXRA) and rs2695121 (LXRB) and ALS phenotypes. Materials and methods: This is a casecontrol study conducted with 115 patients diagnosed with amyotrophic lateral sclerosis (ALS) and 115 control participants without neurodegenerative diseases, matched by sex and age, from the Central-West region of Brazil, between 2017 and 2024. Single nucleotide variants (SNVs) were identified using real-time polymerase chain reaction (qPCR). Results: The LXRA variant rs2279238 showed similar genotypic frequencies in both the case and control groups, indicating no significant association with ALS risk. However, the LXRB variant rs2695121 showed a strong association with ALS phenotypes. In the codominant inheritance model, individuals with the C/T genotype had a 2.5-fold increased risk (p = 0.002), and those with the T/T genotype had a 3.7- fold increased risk (p = 0.005), compared to the C/C wild type. The dominant model (C/T + T/T vs. C/C) indicated a 2.7-fold higher risk (p < 0.001). In the overdominant model (C/T vs. C/C + T/T), heterozygotes had an odds ratio of 1.81 fold increased risk (p = 0.025), suggesting an independent association with disease risk. When analyzing gene-gene interactions, individuals with the heterozygous rs2279238 (LXRA) variant combined with the wild-type rs2695121 (LXRB) genotype exhibited a reduced risk of ALS, with a statistically significant association (OR = 0.31; p = 0.049). Discussion: These findings suggest an association between the LXRB gene and ALS susceptibility and highlight the potential modulatory role of LXRA in reducing risk when in heterozygous form. Further research is warranted to clarify the underlying mechanisms and to explore the role of LXR proteins in ALS pathophysiology. Conclusion: The rs2695121 variant in the LXRB gene is associated with ALS phenotypes. While the rs2279238 variant in LXRA was not directly associated with the disease, its presence in heterozygous form may confer a protective effect when combined with the wild-type LXRB genotype.