In a study of Malaysians of different racial groups, 1,510 sera (908 from Malays, 371 from Chinese and 231 from Indians) were identified for their protease inhibitor (Pi) types. The gene frequencies for the alleles PiM, PiS and PiX in Malays were, respectively, 0.979, 0.015, and 0.007. In Chinese, the frequencies were 0.981, 0.019 and 0.000, and in Indians they were 0.976, 0.24, and 0.000. It is interesting that the usually rare PiX type is found in appreciable frequency in the Malays. Two different types with unusual behavior and obscure origin were also found.
alpha1-Antitrypsin types were determined in 200 individual specimens of Malaysian Macaca irus. We found the pattern B in 76 samples, BC in 116, and C in 8. Assuming that these patterns are determined by codominant alleles at one locus, this distribution constitutes a significant (P less than 0.001) deviation from Hardy-Weinberg equilibrium, because of an excess of BC and low prevalence of C. We found no clear evidence for the presence of alpha1-antitrypsin deficiency comparable to the situation in man.
The distribution of serum alpha 1-protease inhibitor (PI) or alpha 1-antitrypsin (alpha 1AT) subtypes was determined by thin-layer isoelectric focusing in a group of 1233 individuals from six Mongoloid populations of East Asia and Dravidian Indians. The sample comprised 385 Chinese from Singapore and 151 Chinese from the Fujien province; 126 Malays; 243 Filipinos; 112 Thais; 56 Koreans and 160 Dravidian Indians. The frequency of PiM1 ranged from 0.65 in the Thais to 0.81 in the Fujien Chinese. The highest frequency of PiM2 was found in the Dravidian Indians (0.28) followed by the Thais (0.25). The frequency of PiM3 was found to vary from 0.03 to 0.07 in these populations. A low frequency of PiF (0.01 to 0.02) and PiS (0.01 to 0.04) was also observed in the Mongoloid populations but absent in the Indians. The PiZ allele was completely absent in all these populations. The phenotypic distribution of PI subtypes was at Hardy-Weinburg equilibrium in all the populations.
The objective of the present study was to review published surveys on allelic frequencies S and Z in countries outside Europe to evaluate the validity of the reported data. Studies on the topic, published from 1965 to May 2001, were retrieved using MEDLINE and bibliographic reference consultations. The criteria for the selection of the studies were the following: 1) sample size >or=250 individuals; 2) alpha1-antitrypsin phenotype determination performed by means of crossed antigen-antibody, isoelectric focusing in polyacrylamide gels, or polymerase chain reaction (PCR); 3) PI type determination performed without any previous screening procedure; 4) S and Z 95% CI of the reported outcomes within the limits of a calculated coefficient of variation. Forty-three out of 85 studies comply with the established criteria for being analysed. Worldwide maps of geographical distributions of PI S and PI Z frequencies have been designed by the authors by adding the data provided by these 43 selected studies to the 70 reported in a recent European meta-analysis.
Missense mutations in the TP53 tumor-suppressor gene inactivate its antitumorigenic properties and endow the incipient cells with newly acquired oncogenic properties that drive invasion and metastasis. Although the oncogenic effect of mutant p53 transcriptome has been widely acknowledged, the global influence of mutant p53 on cancer cell proteome remains to be fully elucidated. Here, we show that mutant p53 drives the release of invasive extracellular factors (the 'secretome') that facilitates the invasion of lung cancer cell lines. Proteomic characterization of the secretome from mutant p53-inducible H1299 human non-small cell lung cancer cell line discovered that the mutant p53 drives its oncogenic pathways through modulating the gene expression of numerous targets that are subsequently secreted from the cells. Of these genes, alpha-1 antitrypsin (A1AT) was identified as a critical effector of mutant p53 that drives invasion in vitro and in vivo, together with induction of epithelial-mesenchymal transition markers expression. Mutant p53 upregulated A1AT transcriptionally through the involvement with its family member p63. Conditioned medium containing secreted A1AT enhanced cell invasion, while an A1AT-blocking antibody attenuated the mutant p53-driven migration and invasion. Importantly, high A1AT expression correlated with increased tumor stage, elevated p53 staining and shorter overall survival in lung adenocarcinoma patients. Collectively, these findings suggest that A1AT is an indispensable target of mutant p53 with prognostic and therapeutic potential in mutant p53-expressing tumors.
It is known that alpha1-antitrypsin deficiency is associated with emphysema in adults and liver cirrhosis in neonates. The phenotypes PiZZ and PiSZ are considered to be high risk groups. alpha1-antitrypsin deficiency is one of the most common lethal congenital disorders in Europe and the USA, occurring in approximately 1 in 2,000 caucasians of North European descent. Studies in Malaysia have found that the phenotypes PiZ and PiS are present in our population. Out of 950 samples analyzed, it was found that 10 samples were shown to be apparently Z homozygous phenotype. The phenotype is determined by high resolution isoelectrofocusing on an ultra-thin polyacrylamide gel embedded with narrow range Pi phamarlyte. The isoelectrofocused bands are confirmed by immunofixation and the plasma alpha1-antitrypsin levels determined by electroimmunoassay. The abnormal phenotypes are further confirmed by polymerase chain reaction using allele specific oligonucleotides.