Hedgehog Interacting Protein (HHIP) polymorphisms involved in early chronic obstructive pulmonary disease (COPD) - 09/03/22

COPD, the third leading cause of death worldwide, is an under-diagnosed major public health issue without any curative treatment available. Early onset of the disease — under 50 years old in individuals with clinical criteria and 10 or more pack-years smoking history — is inevitably associated with an increased risk of acute respiratory hospitalizations and early death. Many single nucleotide polymorphisms (SNPs) near HHIP gene in 4q31 were previously associated with COPD in multiple genome wide association studies (GWAS). HHIP encodes for an evolutionarily highly conserved physiological inhibitor of the Hedgehog signaling pathway, critical to several developmental processes.

We selected from GWAS published studies 12 SNPs near HHIP considered as the most significantly associated with COPD and its severity, emphysema, and lung function impairment (rs1032295; rs12504628; rs13147758; rs1489759; rs1828591; rs1980057; rs13118928; rs6537296; rs1542725; rs13141641; rs7654947; rs11100865). Using amplification-refractory mutation system (D-ARMS), we performed a double-allele specific multiplex PCR on DNA samples to determine the 12 SNPs. DNA was extracted from blood samples of 327 COPD patients included in the French multicentric university hospital-based cohort untitled COBRA. Clinical data was prospectively collected from 2009 to 2021.

We have characterized the distribution of the 12 SNPs in our whole sample (n=327). The first results indicate an association between rs1980057C and the presence of emphysema (OR=1.69 [1.03–2.78], p=0,04). Moreover, in a well identified subgroup of 45 patients, rs6537296A tended to be associated to an early onset of the disease before 50 years old (OR=0,26 [0.07–1.05], p=0,06). We found the same trend in the whole sample for rs1032295G and rs13141641C.

SNPs near HHIP are likely to be associated with early COPD and emphysema. Further analyses are on the way focusing on haplotypes that could be involved in these phenotypes. Identifying this disadvantageous genetic background in young smokers could lead to prevent COPD even before its pathological manifestations. Hedgehog pathway could be a plausible pharmacological target in COPD.