Identificação de mecanismos genéticos e imunológicos associados ao uso nocivo de álcool em uma população latino-americana miscigenada

Abstract

Introduction: Harmful use of alcohol (HUA) is a public health problem that imposes considerable costs on healthcare systems worldwide. Ethanol consumption affects the quality of life of users, leading to a range of mental and physical health issues. Alcohol-related disorders are complex conditions influenced by various factors, such as alterations in neurotransmission systems, immune/inflammatory mediators, and genetic variants. These disorders have an estimated heritability of 50% to 60%. Genome-wide association studies have revealed numerous genetic variants associated with alcohol-related phenotypes, particularly in drug metabolism-related genes. However, most of these studies have focused on populations of European or Asian ancestries, limiting potential extrapolations to other ethnic groups. Objective: To investigate genetic/immunogenetic mechanisms associated with HUA in admixed Latin American individuals. Methods: The Alcohol Use Disorder Identification Test (AUDIT) was used to assess the risk of HUA in 2,840 individuals from the city of Pelotas (Brazil), in a cross-sectional study design. The participants were genotyped for 2.3 million Single Nucleotide Variants (SNVs) using the Illumina HumanOmni 2.5-8v1 BeadChip platform, followed by genotype imputation. Ancestry patterns were investigated through Principal Component Analysis and ADMIXTURE method. Genetic association analyses were conducted using multivariate logistic regression. The potential functional implications of variants associated with HUA were evaluated through in silico analyses. Additionally, pathway enrichment and interaction analyses were performed to identify mechanisms potentially involved in HUA. Results: Ancestry analyses revealed the admixed pattern of the Pelotas population. Individuals with high risk of HUA exhibited significantly higher median European ancestry compared to low/moderate-risk participants (0.84 and 0.82, respectively; p = 2.13x10-2). Notably, a significant association of the HUA phenotype was identified with an intronic variant in the Cytochrome P450 Family 4 Subfamily B Member 1 (CYP4B1) gene (rs1097611; [p = 4.88x10-8, odds ratio (OR) = 1.8, confidence interval (CI) = 1.46-2.23]. Several variants in linkage disequilibrium with rs1097611 may have functional implications at the locus and are associated with differential CYPB1 gene expression in multiple human tissues. A suggestive association (5x10-8 < p < 10-5) was also observed with an SNV located in the Vav Guanine Nucleotide Exchange Factor 1 (VAV1) gene (p = 6.33x10-6, OR = 3.16, CI = 1.92-5.20), which encodes a product with immune function. Finally, multiple pathways related to nervous and immune systems are involved in HUA. Conclusion: Taken together, these findings support the multifactorial nature of HUA, suggesting the involvement of the immune system and neurotransmission pathways on drug consumption behaviors. Studies like this, with individuals from underrepresented ethnic groups, are essential to identify new variants associated with HUA.