Context:
Early and severe phenotypes of COPD carry the worst prognosis and might find their roots during lung development. Some very significant single nucleotide polymorphism (SNP) are found in 4q31 near HHIP, encoding Hedgehog signaling?s highly conserved physiological inhibitor. The purpose of this study was to identify if SNPs near HHIP could be associated with severe early onset of COPD.

Method:
Blood samples extracted-DNA from 402 French COPD patients included in the multicenter COBRA cohort from 2009 to 2021 were analyzed. Groups were divided into four quartiles based on first visit-age. Bi-allelic specific multiplex PCR was performed using the innovative amplification refractory mutation system 'ARMS' to identify 12 SNPs selected from genome-wide association studies. Serum HHIP protein levels were also assessed by ELISA.
Results:
Mean FEV1 was 33% and mean age 70 years old. We showed an association between early onset of COPD (first visit before 58 years ago) and the homozygous minor allele G rs13147758 (OR 0.49 CI95% [0.35-0.97] p 0.04). HHIP serum levels in minor allele carriers were significantly lower. A similar trend was observed for rs1032295G and rs13141641C. In addition, baseline emphysema was associated with rs1980057C (OR 0.59 CI95% [0.36?0.97], p 0.04).

Conclusion:
This study provides new insights into the pathophysiological mechanisms of early COPD and strengthens genotype/phenotype relationships. Identifying this unfavorable genetic background in young smokers may prevent COPD before it becomes clinically apparent. Hedgehog may represent a new therapeutic approach for COPD.