ABCMdb

ABCA3 p.Ala1086Asp

Predicted by SNAP2:	C: N (82%), D: N (78%), E: N (82%), F: N (66%), G: N (93%), H: N (87%), I: N (82%), K: N (82%), L: N (78%), M: N (82%), N: N (87%), P: N (82%), Q: N (87%), R: N (82%), S: N (93%), T: N (93%), V: N (82%), W: D (63%), Y: N (72%),
Predicted by PROVEAN:	C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Heterozygosity for E292V in ABCA3, lung function a... Respir Res. 2012 Aug 6;13(1):67. Baekvad-Hansen M, Nordestgaard BG, Dahl M
Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals.
Respir Res. 2012 Aug 6;13(1):67., [PMID:22866751]

Abstract [show]
ABSTRACT: BACKGROUND: Mutations 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. 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. 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. RESULTS: In 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 alpha1-antitrypsin ZZ homozygotes. CONCLUSION: Our 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.

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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
14 In contrast, the A1086D mutation was associated with increased FEV1 % predicted (p = 0.03). Login to comment
64 It was not possible to design TaqMan genotyping assays for two of the mutations (A320T and A1086D), and genotyping for these variants was instead performed using the LightScanner (Additional file 3). Login to comment
77 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
92 P-values are by Student`s t-test. Lung function according to surfactant protein-B 121ins2 heterozygosity and α1-antitrysin ZZ homozygosity serve as positive controls. Numbers of individuals with surfactant protein-B 121ins2 heterozygosity and α1-antitrypsin ZZ homozygosity differ slightly from the number of individuals with ABCA3 genotypes due to different number of study subjects available for analysis within the study period In contrast, A1086D heterozygotes had increased FEV1%predicted (p = 0.03) and FVC%predicted (p = 0.008) compared with wildtypes, whereas the FEV1/FVC ratio showed no statistical significant difference (p = 0.51). Login to comment
105 Due to lack of events among A320T, A1086D and S1262G heterozygotes, we were not able to calculate risk of COPD for these variants. 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
141 The phenotype in E292V carriers was previously reported to range from minimal changes on lung biopsy and no symptoms to severe fatal lung disease [8,9]. Login to comment
143 Tobacco smoking [23] and unidentified mutations in surfactant protein-C [24,25], ABCA3 [26], and surfactant protein-B could be risk factors of additionally impaired surfactant function in E292V heterozygotes; although the latter risk factors are probably less prevalent in the general population as compared with tobacco smoking. Login to comment
144 Because participants in the Copenhagen City Heart Study smoked more tobacco than participants from the Copenhagen General Population Study we speculate that the difference in smoking habits between the two cohorts could partly contribute to the different results observed for E292V in the two cohorts. Login to comment
148 However, none of these mutations were associated with lung function or risk of COPD, except for the novel A1086D mutation. Login to comment
150 However, the small number of A1086D heterozygotes (n = 4) makes this finding highly insecure. Login to comment
6 In contrast, the A1086D mutation was associated with increased FEV1 % predicted (p = 0.03). Login to comment
58 It was not possible to design TaqMan genotyping assays for two of the mutations (A320T and A1086D), and genotyping for these variants was instead performed using the LightScanner (Additional file 3). Login to comment
71 H86Y, A320T and A1086D were novel variants, whereas E292V, P766S, S1262G and R1474W have been described previously. Login to comment
84 In contrast, A1086D heterozygotes had increased FEV1 % predicted (p = 0.03) and FVC % predicted (p = 0.008) compared with wildtypes, whereas the FEV1/FVC ratio showed no statistical significant difference (p = 0.51). Login to comment
97 Due to lack of events among A320T, A1086D and S1262G heterozygotes, we were not able to calculate risk of COPD for these variants. 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