Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals

Abstract

BackgroundMutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population.MethodsWe screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n = 10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study.ResultsIn the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV1 % predicted compared with noncarriers (t-test: p = 0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEV1 % predicted (p = 0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p = 0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and α1-antitrypsin ZZ homozygotes.ConclusionOur results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.

Plasma pro-surfactant protein B and lung function decline in smokers

“…Murine models completely deficient in SFTPB die soon after birth from respiratory failure [26] and humans with frameshift mutations in the SFTPB gene develop neonatal respiratory distress [27,28]. Partial deficiencies in SFTPB may also be problematic.…”

Cryo-EM structures of the human surfactant lipid transporter ABCA3

“…Replacement of these two residues by proline (L101P or L982P variant) would likely cause protein-folding defects, which is consistent with the reported misfolding and abnormal intracellular localization of both variants (defined as type I mutations) ( 44 – 46 ). The most frequent ABCA3 missense variant in humans, E292V ( 47 ), is positioned within the coupling helix IH2 of TMD1 (Fig. 5C), located distal to the ATP hydrolysis site, and might be involved in the interdomain coupling between TMD1 and NBD1 during the catalytic cycle.…”

Structure-Based Understanding of ABCA3 Variants

“…Our 3D model improved understanding of the impact of two IH2 frequent variants. E292V is the most frequent missense mutation of ABCA3 (global 0.23% allelic frequency gnomAD, going up to 0.7% in the Danish population) [ 3 , 22 ]. If the acidic property at this position is well conserved in the ABCA1-A4 subgroup, this is less evident in the second subgroup, to which ABCA3 belongs.…”