Highlight
1. Genome-wide association study in East Asian cohorts identified key IPF risk loci on chromosomes 4, 5, 6, and 11, mirroring known European loci.
2. The MUC5B promoter variant, a dominant IPF genetic risk factor, is present in East Asians and arises independently of European admixture.
3. Together, common variants (excluding MUC5B) contribute approximately 25% of IPF risk in East Asian populations.
4. Findings suggest conserved genetic mechanisms underlying IPF across ancestries, supporting shared pathobiology and potential for cross-population therapeutic strategies.
Study Background
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease characterized by excessive scarring of lung tissue. The disease predominantly affects older adults and leads to respiratory failure. Despite advances in understanding environmental and clinical risk factors, the precise etiology of IPF remains elusive. Increasing evidence implicates genetic predisposition as an important component of disease susceptibility and progression.
Previous genetic studies, mainly conducted in populations of European descent, have identified multiple common and rare variants associated with IPF risk, prominently including variants at the MUC5B locus. However, the genetic architecture of IPF in populations with East Asian ancestry, where allele frequencies and population history differ substantially, has been inadequately studied. This gap hinders comprehensive understanding of IPF pathogenesis globally and limits the development of inclusive precision medicine approaches.
Study Design
This investigation is a genome-wide association study (GWAS) leveraging patient cohorts of East Asian ancestry—specifically from Japan and Korea—with 1026 IPF patients and 1723 controls without the disease. Both cohorts underwent independent GWAS analyses, followed by meta-analysis combining results to enhance statistical power.
Genotype data were analyzed for common variants across the genome, with emphasis on known IPF-associated loci from prior European studies. Additional statistical methodologies included restricted maximum likelihood (REML) to estimate single nucleotide polymorphism (SNP)-based heritability, reflecting the proportion of disease risk attributable to common genetic variation, and local ancestry inference on chromosome 11 to assess whether the MUC5B risk allele in East Asians resulted from gene flow from European populations.
Key Findings
The study identified four chromosomal loci significantly associated with IPF risk in East Asians, corresponding precisely to previously reported loci in Europeans:
- Chromosome 4 (FAM13A, rs7690839): This locus reached genome-wide significance, confirming its role in IPF susceptibility across ancestries.
- Chromosome 5 (TERT, rs7734992): Variants in the telomerase reverse transcriptase gene, previously implicated in IPF and telomere biology, were associated with elevated risk.
- Chromosome 6 (DSP, rs2076295): Desmoplakin gene variants known for their role in epithelial integrity contribute to disease risk similarly in East Asians.
- Chromosome 11 (MUC5B, rs35705950): The promoter variant in MUC5B remains the most robust common variant associated with IPF risk, with an effect size and risk allele frequency distinct from, yet highly correlated with, European data.
Notably, the analysis determined that the presence of the MUC5B risk allele in East Asians is not attributable to European admixture but likely represents an independent origin or long-standing presence within this population.
Heritability estimation revealed that, excluding the MUC5B variant, common genetic variants explain approximately 25% of IPF risk in these East Asian cohorts, underscoring the substantial contribution of polygenic factors beyond the major known allele.
Expert Commentary
This study provides compelling evidence that the genetic risk landscape for IPF is largely shared between East Asian and European populations, despite demographic and evolutionary differences. Understanding similar disease mechanisms across ancestries enhances the potential translational relevance of genetic findings and novel therapeutic targets.
However, differences in allele frequencies and effect sizes underscore the importance of inclusive genetic studies in diverse populations to accurately model disease risk and inform clinical risk prediction. The report also highlights the complexity of MUC5B-associated risk, suggesting population-specific evolutionary histories.
Limitations include a relatively modest sample size compared to European cohorts, which may affect the power to detect population-specific or rare variant associations. Further research integrating whole-genome sequencing and functional studies is essential to delineate causative variants and their biological impact.
Conclusion
This comprehensive GWAS affirms that idiopathic pulmonary fibrosis genetic risk loci are conserved between East Asian and European populations. The replication of associations at FAM13A, TERT, DSP, and MUC5B loci suggests a shared genetic etiology, although differences in allele distribution and effect sizes warrant tailored risk assessment in clinical practice.
These findings strengthen the argument for collaborative international genetic research efforts and highlight the need to incorporate diverse populations in IPF research for equitable advances in understanding and managing this devastating disease.
Funding and Clinical Trials
The study was supported by multi-institutional collaborations across Japan, Korea, and the United States. Specific funding sources and trial registrations were not detailed in the abstract but are likely documented in the full publication.
References
1. Peljto AL, Furusawa H, Puthenvedu D, et al. Idiopathic pulmonary fibrosis risk loci in East Asian populations mirror those of European populations. Am J Respir Crit Care Med. 2026;212(7):1522-1532. PMID: 42085270.
2. Fingerlin TE, Murphy E, Zhang W, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45(6):613-620.
3. Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503-1512.