COPD in individuals with the PiMZ alpha-1 antitrypsin genotype

Abstract

Since the discovery of severe alpha-1 antitrypsin deficiency as a genetic risk factor for emphysema, there has been ongoing debate over whether individuals with intermediate deficiency with one protease inhibitor Z allele (PiMZ, or MZ) are at some risk for emphysema. This is important, because MZ individuals comprise 2-5% of the general population. In this review we summarise the evidence about the risks of the MZ population to develop emphysema or asthma. We discuss the different study designs that have tried to answer this question. The risk of emphysema is more pronounced in case-control than in population-based studies, perhaps due to inadequate power. Carefully designed family studies show an increased risk of emphysema in MZ smokers. This is supported by the rapid decline in lung function of MZ individuals when compared to the general population after massive environmental exposures. The risk of asthma in MZ subjects is less studied, and more literature is needed before firm conclusions can be made. Augmentation therapy in MZ individuals is not supported by any objective studies. MZ smokers are at increased risk for emphysema that is more pronounced when other environmental challenges are present.

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

“…The frequency of MZ individuals in Australia and New Zealand is similar to the 2–5% reported in other populations with significant European descent but it may be greater than this among New Zealand Māori and lower among Australian Aboriginal peoples . Serum AAT levels are reduced to approximately 60% of those found in MM individuals .…”

“…The frequency of MZ individuals in Australia and New Zealand is similar to the 2-5% reported in other populations with significant European descent but it may be greater than this among New Zealand M aori and lower among Australian Aboriginal peoples. 7,121,122 Serum AAT levels are reduced to approximately 60% of those found in MM individuals. 4 The risk of COPD in MZ compared with MM individuals has previously been investigated with mixed results but more recent studies have provided strong evidence of increased risk in cigarette-smoking members of this population.…”

Alpha-1 Antitrypsin Deficiency and Lung Transplantation: A Clinical Case

“…In the last 20 years, AAT augmentation therapy has emerged as an effective and specific tool to reduce the progression of emphysema in patients with Z allele homozygosity of the SERPINA1 gene [11]. To date, there is no evidence to support augmentation therapy for heterozygous patients, even if the presence of emphysema that is out of proportion to age and smoking suggests a possible role for therapy in this setting [12]. However, augmentation therapy is not thought to halt progressive deterioration of lung function; for this reason, patients with severe AATD-related lung disease should undergo specific evaluation for lung transplant (LTX).…”

Potential Biochemical Markers of Chronic Bronchitis and Bronchial Asthma. Current State of the Problem

“…По данным Европейского респираторного общества, в странах Европы распространенность дефицита А1АТ варьирует в пределах одного случая на 1800-2500 новорожденных, что составляет около 125 тыс. человек [31].…”

“…Пятый экзон -область частых мутаций, связанных с недостаточностью А1АТ. Аллели наименованы от A до Z; аномальными считаются S и Z, наследование осуществляется по кодоминантному типу: фенотип определяют обе аллели [31]. Измененный А1АТ накапливается в гепатоцитах ввиду невозможности прохождения через цитоплазматическую мембрану из-за большей, чем у нормального белка, молекулярной массы, что приводит к апоптозу клеток [5].…”