CHIA – Asthma

Recent evidence implicates CHIA (HGNC:17432) in the pathogenesis of asthma (MONDO_0004979) through both genetic association studies and functional assessments. In a case‑report study of Turkish children with asthma, a ten base pair insertion in the 5′‑UTR region of exon 2 was found to be significantly associated with reduced forced expiratory volume (FEV₁) (PMID:21511453). This finding suggests that noncoding variants in CHIA may modulate gene expression and contribute to the clinical severity of asthma in distinct populations.

A multi‑patient study further substantiated the association by identifying multiple CHIA polymorphisms, including the novel missense variant c.49A>C (p.Lys17Arg), which demonstrated significant association with asthma in both pediatric and adult cohorts (PMID:16179638). The haplotype analyses in this study provided compelling genetic evidence, revealing strong correlations between specific CHIA alleles and disease status across diverse populations.

Complementary functional studies have elucidated the biological impact of CHIA variants on the enzymatic activity of acid mammalian chitinase (AMCase). Experimental assays, including promoter reporter assays and biochemical kinetic analyses, have shown that certain CHIA haplotypes lead to altered pH activity profiles and substrate binding, ultimately influencing the downstream Th2 inflammatory responses observed in asthma (PMID:19435888; PMID:27702777).

The convergence of genetic and functional evidence, including replication across independent cohorts and mechanistic studies in cell‐based and murine models, underpins a strong association between CHIA variants and asthma susceptibility. Although some studies have noted population‐specific effects, the overall data robustly support that CHIA plays a critical role in regulating AMCase expression and activity, thereby modulating asthma severity.

Additional experimental evidence exceeding the ClinGen scoring cap further reinforces the role of CHIA as a modifier of pulmonary function and a potential target for precision medicine approaches in asthma. The integration of case reports, large replication studies, and detailed functional assays provides a comprehensive framework that enhances diagnostic decision‑making and informs targeted commercial applications.

Key take‑home message: CHIA is strongly implicated in asthma through multi‑cohort genetic associations and functional alterations in AMCase activity, underscoring its clinical utility as a biomarker and potential therapeutic target.

References

• Respiratory medicine • 2011 • The effects of an insertion in the 5'UTR of the AMCase on gene expression and pulmonary functions PMID:21511453
• American journal of respiratory and critical care medicine • 2005 • Polymorphisms and haplotypes of acid mammalian chitinase are associated with bronchial asthma PMID:16179638
• The Journal of biological chemistry • 2009 • Differential enzymatic activity of common haplotypic versions of the human acidic Mammalian chitinase protein PMID:19435888
• Molecular biology and evolution • 2016 • Loss and Gain of Human Acidic Mammalian Chitinase Activity by Nonsynonymous SNPs PMID:27702777

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