HHIP polymorphisms involved in emphysema and early onset COPD

The well-known genetic influence in COPD and emphysema appears relevant to the early severe phenotype that roots in lung development and carries poor prognosis. Some highly associated to lung function and COPD single nucleotide polymorphisms (SNPs) locate in 4q31 with Hegdehog9s highly conserved inhibitor gene (HHIP). Its role in early-onset is unknown altough clinical studies and murine models confirmed it in COPD and emphysema development. The study aimed to validate, in French COPD patients, the involvement of SNPs near HHIP locus in emphysema occurrence and investigate their link to severe early-onset disease. We used DNA extracted from the blood samples of 380 patients, who were part of the multicenter French 9COBRA9 cohort from 2009 to 2021. Groups were sorted into 4 quartiles by initial visit age. We performed an innovative amplification refractory mutation system (ARMS) bi-allelic specific multiplex PCR to detect 12 selected SNPs. Serum HHIP levels were ELISA-assessed. Median FEV1 was 56%, while 37% of patients had emphysema. rs1980057 appeared protective against emphysema (OR0.62 CI95%[0.45-0.86] p=0.004) and linked to lower serum levels for CT and TT alleles carriers against CC (p=0.02). Roughly, early-onset patients (n=82) experienced lower protein levels than others (p<0.01). Two SNPs (rs1032295 and rs10519717) tend to be linked to early-onset (OR1.62 CI95%[1.03-2.55] p=0.035 and OR1.99 CI95%[1.08-3.67] p=0.02 respectively) but lost significance after correction. This research provides new insights into early COPD mechanisms and strengthens genotype/phenotype connections. Identifying genetic background in young smokers may prevent COPD before its clinical onset. Hedgehog pathway shows therapeutic potential.