SERPINA1 – Modifier of Liver Disease in Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder caused by CFTR mutations, with variable clinical severity influenced by modifier genes. The SERPINA1 gene (encoding alpha-1-antitrypsin) has been identified as a genetic modifier of CF-associated liver disease, particularly portal hypertension. Heterozygosity for the Z allele of SERPINA1 is associated with increased risk of severe liver involvement in CF patients (PMID:19738092).

In a two-stage case‐control study of CF patients with severe liver disease and portal hypertension (CFLD), the SERPINA1 Z allele (c.1096G>A (p.Glu366Lys)) was enriched in 124 CFLD cases versus 843 CF controls (OR 4.72, P = 3.3 × 10⁻⁶) and replicated in 136 CFLD versus 1088 non-CFLD CF patients (OR 3.42, P = 1.4 × 10⁻³), with a combined OR of 5.04 (PMID:19738092). No family segregation data are available for this modifier effect.

Variant spectrum in CF cohorts includes the classical Z allele (c.1096G>A (p.Glu366Lys)) and less common S or null alleles; the Z allele acts in heterozygous state to worsen liver phenotype. Carrier frequency of SERPINA1 Z in CF patients approximates that in the general population (~2–5%), but its co-inheritance with CFTR mutations markedly elevates liver disease risk.

Functional studies demonstrate that the Z variant induces polymerization and retention of misfolded alpha-1-antitrypsin in hepatocyte endoplasmic reticulum, triggering apoptosis and fibrogenesis. In PiZ transgenic mice, Z protein accumulation correlates with caspase activation and hepatocellular injury, mirroring human CF liver pathology (PMID:17886264).

No conflicting studies have convincingly refuted the association, though preliminary small cohorts failed to show correlation between SERPINA1 variants and CF liver markers. Overall, genetic and experimental data support a Moderate level of clinical validity for SERPINA1 as a CF modifier gene.

Key Take-home: Testing for SERPINA1 Z allele in cystic fibrosis patients enables early identification of individuals at elevated risk for severe liver disease with portal hypertension.

References

• JAMA • 2009 • Genetic modifiers of liver disease in cystic fibrosis PMID:19738092
• Hepatology • 2007 • Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model PMID:17886264

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