Resumo:
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.
