A functional genetic variant in the CYP4V2 gene appears to increase asthma susceptibility by altering gene activity through DNA methylation and disrupting key inflammatory pathways. The details of that discovery were outlined in the paper, “A Functional Variant of CYP4V2 Contributes to Asthma Susceptibility Through Methylation-Mediated Regulation of the Arachidonic Acid Pathway,” recently published in the Journal of Asthma and Allergy.
The multi-omics study was conducted using data from the Singapore/Malaysia Cross-Sectional Genetics and Epidemiological Study (SMCSGES) cohort and sheds light on how genetic and epigenetic factors may influence asthma development. Researchers found that elevated expression of the CYP4V2 gene in peripheral blood mononuclear cells was associated with a higher risk of asthma. Further analysis identified a single nucleotide polymorphism (SNP), rs2276921, as the only genetic variant significantly linked to both increased CYP4V2 expression and greater asthma susceptibility. Individuals carrying the variant's minor G allele were more likely to exhibit higher gene activity and increased disease risk, according to the study’s authors.
Investigators also discovered that this genetic variant influences DNA methylation at two promoter-region CpG sites, cg23232844 and cg11969330, which act as regulatory switches controlling CYP4V2 expression. Laboratory promoter assays confirmed that these methylation sites suppress gene activity, providing evidence that the asthma-associated variant may exert its effects through epigenetic regulation.
Researchers noted that the findings point to a previously underexplored role for CYP4V2 in the arachidonic acid (AA) pathway, a critical network involved in inflammatory responses associated with asthma. They observed that increased CYP4V2 expression was inversely associated with PTGER2 and ALOX5AP, genes that play important roles in prostaglandin and leukotriene signaling pathways.
According to the study, these relationships suggest that CYP4V2 may alter the balance of inflammatory lipid mediators, potentially contributing to airway inflammation and asthma symptoms. Although downstream lipid products were not directly measured in the study, the results support the hypothesis that CYP4V2 participates in lipid metabolism processes linked to respiratory disease.
Researchers said the discovery could have implications for future asthma diagnosis and treatment strategies. By linking a specific genetic variant, DNA methylation patterns and inflammatory pathways to asthma risk, the study highlights CYP4V2 as a promising candidate biomarker and therapeutic target.
However, the authors cautioned that the work has limitations. The analysis relied on blood immune cells rather than airway tissues, did not directly measure lipid mediators and was based on a cross-sectional study design. They noted that additional validation in larger and more diverse populations will be necessary before the findings can be translated into clinical practice.
