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α1 Antitrypsin (α1AT) is a 52 kDa proteinase encoded by a gene locus Pi on chromosomal segment 14q32.1. It is a natural inhibitor of proteinase 3 (PR3), a neutrophil granular protein and a major autoantigen of antineutrophil cytoplasmic antibody (ANCA). The function of α1AT is in turn restricted by myeloperoxidase (MPO), another autoantigen of ANCA. The interplay between the enzymes, inhibitors, and the autoantibodies is implicated in the dynamics of the vasculitic process,1 resulting in a whole spectrum of clinical conditions ranging from systemic granulomatous diseases to kidney limited glomerulonephritis. There have been reports of the correlation of specific α1AT alleles, notably PiZ, with ANCA.2-4 These were largely studies of white subjects, which may not necessarily be extrapolated to all populations.
α1AT variant phenotypes may have predisposed to PR3-ANCA, but the same association may not exist for MPO-ANCA. In populations with a low prevalence of α1AT variant phenotypes, the pattern of ANCA could differ from that in white subjects where such variants prevail. We set out therefore to establish the distribution of α1AT in patients with the two main forms of ANCA (anti-PR3 positive and anti-MPO positive). Blood samples of patients with vasculitis received at the immunology section of the Department of Pathology, Queen Mary Hospital, Hong Kong, were tested for ANCA by indirect immunofluoresence, followed by enzyme linked immunosorbent assays (ELISA) for anti-PR3 and anti-MPO. α1AT phenotypes were determined by isoelectric focusing, the results of which were compared with those of healthy Chinese adults.
A total of 157 samples from ANCA+ (either anti-MPO or anti-PR3 positive by ELISA) patients were evaluated, 60 (38%) of which were positive for anti-PR3 and 97 (62%) for anti-MPO by ELISA. All were Chinese patients with a clinical diagnosis of vasculitis. The male to female ratio was 0.76 (0.94 for anti-PR3 positive and 0.67 for anti-MPO positive patients). The mean age of the two groups was 52.4 and 59.4 years, respectively. A total of 103 (66%) were homozygous M, 50 (32%) heterozygous M (for example, M1 M2), and 4 (3%) heterozygous for M and a variant allele. Tables 1 and 2 show the allelic and phenotypic frequencies. In the healthy controls (n=1085), 717 (66.1%) were homozygous for an M phenotype. Allelic variants were rare, accounting for only 0.7% of all alleles. The α1AT deficiency variant PiZ was absent in both the study group and the healthy control group. There was no significant difference in the proportion of homozygous and heterozygous M phenotypes between the normal and the ANCA+ group (exact χ2 test, p=0.56) and between anti-PR3 and anti-MPO (exact χ2 test, p=0.80). ANCA+ patients had a higher proportion of variant alleles, but this did not reach significance (1.26% v 0.70%; exact χ2 test, p=0.10).
The rarity of the PiZ allele in oriental5 and black populations6 has been previously reported, a finding which is confirmed for Chinese patients in this study. We found no association of α1AT variant phenotypes with ANCA in Chinese patients. It is interesting to note the higher number of anti-MPO positive patients in the study group. In a separate study the anti-MPO to anti-PR3 ratio in Chinese patients diagnosed over a defined period was 1.4:1 (the reverse of the situation in white populations, where PR3-ANCA positive Wegener's granulomatosis is much more common).7 Even for the Chinese patients who tested positive for PR3-ANCA, the positive predictive value for Wegener's granulomatosis was less than 25%. The low prevalence of α1AT variant phenotypes may be one factor behind the uncommon presence of anti-PR3 in Chinese people. We conclude that α1AT does not have a significant role in ANCA associated diseases in southern Chinese among whom anti-MPO predominate.