Single‑nucleotide polymorphism rs6592645 confers asthma risk through regulating LRRC32 expression

Area of Science:

• Genetics
• Molecular Biology
• Respiratory Medicine

Background:

• Asthma exhibits genetic predisposition, with SNP rs7130588 previously linked to the disease via GWAS.
• SNP rs6592645 is in linkage disequilibrium with rs7130588, suggesting it may also be associated with asthma.
• The precise causal SNP and its mechanism in asthma pathogenesis remain unclear.

Purpose of the Study:

• To identify the causal single-nucleotide polymorphism (SNP) associated with asthma.
• To elucidate the regulatory mechanism of the identified SNP on gene expression.
• To investigate the role of LRRC32 in asthma development.

Main Methods:

• Dual-luciferase assays were used to assess the functional impact of SNPs.
• Chromosome conformation capture (3C) identified interactions between regulatory elements and gene promoters.
• Gene expression was quantified in lung tissue, and chromatin immunoprecipitation (ChIP) identified protein-DNA interactions.

Main Results:

• SNP rs6592645, not rs7130588, demonstrated allele-specific regulatory activity in luciferase assays.
• The enhancer region containing rs6592645 interacts with the promoter of LRRC32.
• LRRC32 expression is elevated in asthma patients and genotype-dependent, with TCF3 binding to the rs6592645 region.

Conclusions:

• SNP rs6592645 is likely the causal variant influencing asthma susceptibility.
• rs6592645 regulates LRRC32 expression, implicating this gene in asthma pathogenesis.
• TCF3 interaction with rs6592645 provides insight into the molecular mechanism of asthma genetic risk.