doi: 10.1161/01.ATV.0000097980.11819.93
© 2003 American Heart Association, Inc.
Letters to the Editor |
Risk of Ischemic Heart and Ischemic Cerebrovascular Disease Is not Increased in S, Z, and 11478A 
1-Antitrypsin Carriers of The Copenhagen City Heart Study
Department of Clinical Biochemistry, Herlev and Copenhagen University Hospitals; and The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen, Denmark
To the Editor:
In a study of 395 men, Talmud and coworkers1 found a trend toward increased atherosclerosis progression in 
1-antitrypsin deficiency S and Z carriers and a significantly increased atherosclerosis progression in 1-antitrypsin 11478A carriers compared with noncarriers. As opposed to this, recent studies suggest the opposite, a protective role of 1-antitrypsin deficiency against atherosclerotic disorders.2,3
In our study of 11,315 men and women, severe ZZ 1-antitrypsin deficiency and intermediate MZ deficiency were associated with reduced blood pressure, and MZ was also associated with reduced risk of ischemic cerebrovascular disease (ICVD) and ischemic heart disease (IHD).2 The MS genotype did not affect blood pressure or risk of IHD and ICVD in our study.
We also screened subjects for the less severe 11478A variant in the 1-antitrypsin gene4 but never previously reported on risk of IHD and ICVD for this variant. Among men, odds ratios for IHD and ICVD in 11478A carriers versus noncarriers were 0.93 (0.76 to 1.1) and 0.98 (0.72 to 1.3). When these analyses included women, the results were similar to those for men. Thus, in contrast to Talmud et al,1 we were not able to make observations suggesting that 11478A carriers have increased risk of atherosclerotic disease.
Because risk of atherosclerotic disorders was reduced (rather than increased) in 1-antitrypsin–deficient individuals,2,3 the observed increased atherosclerosis progression in Z, S, and 11478A carriers1 does not appear to progress to overt clinical disease in affected individuals. Future studies of progression of atherosclerosis and risk of IHD and ICVD in the severe ZZ 1-antitrypsin genotype are important to explore the relationship between 1-antitrypsin deficiency and risk of ischemic cardiovascular disease in greater detail.
References
1. Talmud PJ, Martin S, Steiner G, Flavell DM, Whitehouse DB, Nagl S, Jackson R, Taskinen M-R, Frick MH, Nieminen MS, Kesäniemi YA, Pasternack A, Humphries SE, Syvänne M. Progression of atherosclerosis is associated with variation in the 1-antitrypsin gene. Arterioscler Thromb Vasc Biol. 2003; 23: 644–649.
2. Dahl M, Tybjærg-Hansen A, Sillesen H, Jensen G, Steffensen R, Nordestgaard BG. Blood pressure, risk of ischemic cerebrovascular and ischemic heart disease, and longevity in 1-antitrypsin deficiency. Circulation. 2003; 107: 747–752.
3. Elzouki A-N, Ahlgren AR, Länne T, Sonesson B, Eriksson S. Is there a relationship between abdominal aortic aneurysms and alpha1-antitrypsin deficiency (PiZ)? Eur J Vasc Endovasc Surg. 1999; 17: 149–154.[CrossRef][Medline] [Order article via Infotrieve]
4. Dahl M, Tybjærg-Hansen A, Lange P, Vestbo J, Nordestgaard BG. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: a longitudinal study of the general population. Ann Intern Med. 2002; 136: 270–279.
Centre for Cardiovascular Genetics, Department of Medicine (P.J.T., R.W., S.E.H.), British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, London, UK, DAIS Project Director (G.S.), The Toronto Hospital, Toronto, Ontario, Canada M5G 2C4, and Division of Cardiology, Department of Medicine (M.S.), Helsinki University Central Hospital, Helsinki, Finland
In Response:
We appreciate the comments raised by Dahl et al in the letter above. However, there are a number of differences in the study design reported in our article published in Arteriosclerosis, Thrombosis, and Vascular Biology1 and that of both Dahl et al2 and Elzouki et al,3 which could have led to discrepancies in the concluded role for alpha-1-antitrypsin (AAT). While our study examined the association of common and rare AAT variants with progression of atherosclerosis in individuals with well defined atherosclerotic disease, the others looked at the occurrence of ischemic heart disease (IHD) or ischemic cerebrovascular disease (ICVD) in individuals who carried rare AAT deficiency genotypes compared with controls. Atherosclerosis progression, IHD, and ICVD are very different disease endpoints, and furthermore, the causes of ischemia are multiple.4 In addition, while our study is a prospective analysis of angiographically defined disease, the other two are case:control analyses. So the disparities are likely in part to be due to the very different phenotypes and clinical endpoints examined. Furthermore, the conclusions from the study by Elzouki et al3 were based on only 6 MZ carriers.
We reported that carriers of the rare PiS and PiZ variants of AAT showed increased progression of angiographically defined coronary atherosclerosis in the LOCAT study of Finnish men. However, the number of these carriers was small (n=14), and our main conclusions were mainly based on the association of the functional AAT 3'UTR variant 11478G>A, showing differences in the change of progression of atherosclerotic disease, which we confirmed in a second study of disease progression, DAIS. In vitro, this site responds to inflammatory stimuli5 and therefore is more likely to be associated with differences in AAT levels in patients with CAD rather than in healthy individuals, which might reflect the negative associations reported by Dahl et al in their letter. In contrast, Dahl et al2 reported a protective effect of the AAT PiZ deficiency state on blood pressure, IHD, and ICVD. The PiS deficiency state, however, showed no such associations, which raises the question as to why carriers of the MS allele, who also show reduced AAT activity and mass, are not protected. In the LOCAT study, we found the carrier frequency of the MZ or MS alleles was as expected for the Finnish population,6 but if these alleles were protective as suggested, one would predict a smaller-than-expected number of carriers in this group of men with defined atherosclerosis. We found no difference in blood pressure in MZ and MS carriers in LOCAT or in a group of 2700 healthy UK men (P.J. Talmud and S. Martin, unpublished data, 2001) and thus cannot confirm the effect seen by Dahl et al.
A recent article in Circulation reported the presence of neutrophil elastase, the substrate for AAT, within the atherosclerotic plaque but not normal arteries,7 which would indicate a role for neutrophil elastase and its inhibitor, AAT, in atherogenesis. However, whether the role of AAT is protective remains to be elucidated. Our study would suggest that, in those who already have the disease, deficiency in AAT leads to a greater progression of the disease, thus indicating a protective role for AAT.
In response to Dahl et al, we agree with their main conclusion, namely that additional studies need to be carried out on larger samples of AAT-deficient patients. Our study and those of Dahl et al2 and Elzouki et al3 are the only reported association studies examining AAT genotype and vascular diseases, therefore highlighting the need for both association and functional studies to elucidate the role of AAT in atherogenesis, CVD, and IHD.
References
1. Talmud PJ, Martin S, Steiner G, Flavell DM, Whitehouse DB, Nagl S, Jackson R, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Humphries SE, Syvanne M. Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene. Arterioscler Thromb Vasc Biol. 2003; 23: 644–649.
2. Dahl M, Tybjaerg-Hansen A, Sillesen H, Jensen G, Steffensen R, Nordestgaard BG. Blood pressure, risk of ischemic cerebrovascular and ischemic heart disease, and longevity in alpha(1)-antitrypsin deficiency: the Copenhagen City Heart Study. Circulation. 2003; 107: 747–752.
3. Elzouki AN, Toth E, Floren CH, Lindgren S, Fork FT, Sjolund K, Walder M, Eriksson S. Alpha1-antitrypsin deficiency may be a risk factor for duodenal ulcer in patients with Helicobacter pylori infection. Scand J Gastroenterol. 2000; 35: 32–35.[CrossRef][Medline] [Order article via Infotrieve]
4. Pezzini A, Vignolo LA, Padovani A. Risk of ischemic cerebrovascular disease in alpha1-antitrypsin deficiency. Circulation. 2003; 108: e62–e63.
5. Morgan K, Scobie G, Marsters P, Kalsheker NA. Mutation in an alpha1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors. Biochim Biophys Acta. 1997; 1362: 67–76.[Medline] [Order article via Infotrieve]
6. Arnaud P, Koistinen J, Wilson GB, Fudenberg HH. alpha-1-Antitrypsin (Pi) phenotypes in a Finnish population. Scand J Clin Lab Invest. 1977; 37: 339–343.[Medline] [Order article via Infotrieve]
7. Dollery CM, Owen CA, Sukhova GK, Krettek A, Shapiro SD, Libby P. Neutrophil elastase in human atherosclerotic plaques: production by macrophages. Circ. 2003; 107: 2829–2836.
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