ABCMdb

ABCA3 p.His86Tyr

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Publications

PMID: 22866751 [PubMed] Baekvad-Hansen M et al: "Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals."

No. Sentence Comment

2 Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals Respiratory Research 2012, 13:67 doi:10.1186/1465-9921-13-67 Marie Bækvad-Hansen (baekvad@gmail.com}) Børge G Nordestgaard (brno@heh.regionh.dk}) Morten Dahl (dahlos2003@yahoo.dk}) ISSN 1465-9921 Article type Research Submission date 23 March 2012 Acceptance date 27 July 2012 Publication date 6 August 2012 Article URL http://respiratory-research.com/content/13/1/67 This peer-reviewed article was published immediately upon acceptance. Login to comment
10 Methods We 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. Login to comment
77 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
88 The observed reductions in pulmonary function were almost similar in absolute numbers to those observed for surfactant protein-B 121ins2, a mutation which in the homozygous state associates with a phenotype somewhat similar to that for E292V compound heterozygosity. Login to comment
96 Individuals heterozygous for H86Y, A320T, P766S, S1262G, or R1474W did not differ from wildtypes in FEV1%predicted, FVC%predicted or FEV1/FVC (p≥0.19). Login to comment
103 For the H86Y, P766S and R1474W mutations, risk of COPD did not deviate significantly from 1.0. Login to comment
126 Figure 3 Lung function according to ATP binding cassette member 3 (ABCA3) E292V, surfactant protein-B 121ins2, and α1-antitrypsin ZZ genotypes in the Copenhagen City Heart Study and Copenhagen General Population Study combined, stratified for smoking status. Login to comment
135 Numbers of individuals with surfactant protein-B 121ins2 heterozygosity and α1-antitrypsin ZZ homozygosity differ slightly from the number of individuals with an ABCA3 E292V genotype due to different number of study subjects available for analysis within the study period Discussion To test whether individuals heterozygous for ABCA3 variants have reduced lung function and increased risk of COPD in the general population, we screened 760 individuals with extreme lung phenotypes for genetic variations in the ABCA3 gene and identified three novel (H86Y, A320T, A1086D) and four previously described variations (E292V, P766S, S1262G, R1474W). Login to comment
145 When statistical power, however, was maximised using the Copenhagen General Population Study or the two studies combined, E292V heterozygotes did not differ from wildtypes in lung function or COPD risk. Login to comment
146 This is an important finding as 1.3 % in the Danish general population has partially reduced ABCA3 function due to E292V, and since this variant has been linked previously with severe chronic lung disease in heterozygous and compound heterozygous E292V carriers [8-10]. Login to comment
152 The second novel mutation, H86Y, is situated in the first extracellular loop of ABCA3. Login to comment
153 Another mutation in this loop, L101P, has been shown to affect ABCA3 protein folding leading to retention of ABCA3 in the endoplasmatic reticulum and subsequent ER stress and apoptosis [27,28], however individuals heterozygous for the H86Y mutation appeared asymptomatic in this study. Login to comment
71 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
95 For the H86Y, P766S and R1474W mutations, risk of COPD did not deviate significantly from 1.0. Login to comment
102 Characteristics did not differ between E292V heterozygotes 60 80 100 120 60 80 100 120 0.6 0.8 Genotype N FEV1 % predicted p FVC % predicted p FEV1/FVC p H86Y Wt 9801 Het 15 0.76 0.91 0.39 E292V Wt 9706 Het 110 0.008 0.04 0.03 A320T Wt 9803 Het 13 0.19 0.27 0.74 P766S Wt 9695 Het 121 0.65 0.42 0.55 A1086D Wt 9802 Het 4 0.03 0.008 0.51 S1262G Wt 9802 Het 14 0.47 0.77 0.53 R1474W Wt 9636 Het 180 0.49 0.20 0.48 SP-B121ins2 Wt 10425 Het 21 0.67 0.68 0.10 b1;1-antitrypsin MM 8082 ZZ 6 0.01 0.55 0.0008 Figure 1 Lung function according to ATP binding cassette member 3 (ABCA3) genotype in the Copenhagen City Heart Study. Login to comment
112 We also stratified our data for smoking status, as did our previous study of surfactant protein-B 121ins2 as a risk factor in COPD [12], but found no significant differences in lung Age adjusted Odds ratio (95% confidence interval) 0.1 1 10 Genotype Participants Events H86Y Wt 9801 1080 Het 15 2 E292V Wt 9706 1063 Het 110 19 P766S Wt 9695 1067 Het 121 15 R1474W Wt 9636 1064 Het 180 18 SP-B121ins2 Wt 10427 1209 Het 21 5 b1;1-antitrypsin MM 8082 927 ZZ 6 3 Multi variate adjusted 0.1 1 10 Figure 2 Risk of COPD according to ATP binding cassette member 3 (ABCA3) genotype in the Copenhagen City Heart Study. Login to comment