Estimated Worldwide Prevalence of Population with AAT Deficiency with MZ Alleles

Surprisingly High Prevalence of MZ Allele Carriers among Seriously Ill Patients

Alpha-1-antitrypsin deficiency (AATD) is an inherited disorder with autosomal codominant inheritance caused by a mutation in the SERPINA1 gene. Currently, more than 120 alleles of this gene have been identified, of which approximately 40% can cause the development of the disease characterized by lung and liver tissue damage (in some genotypes) due to reduced production of serine protease inhibitors. One variant of the disease is the carriage of MZ alleles, where the M allele represents the normal variant of the gene and the Z allele is associated with the production of a defective protein. These individuals express 55% of the normal serum level of alpha-1-antitrypsin.

MZ allele carriage was originally considered a genotype with a mild deficiency associated with negligible or low risk of clinically manifest disease. However, later studies showed that while the risk of lung disease is indeed not increased in non-smokers, smokers have a higher risk of developing chronic obstructive pulmonary disease (COPD). Available evidence also suggests that while MZ allele carriage does not cause liver damage in childhood, several series of patients with end-stage liver damage included in transplant programs have shown surprisingly high prevalence of individuals with MZ alleles.

Moreover, a study published two decades ago estimated that the number of MZ allele carriers exceeded 25 million people, predominantly Caucasians on the European continent.

Analyzed Data

Although the disease is likely only clinically manifested in a small portion of MZ allele carriers, given the expected high prevalence in the population, it can be a significant health problem, especially in individuals with an unhealthy lifestyle. The aim of the epidemiological study was to update data on the prevalence of MZ alleles and the rate of smoking in the global population.

Data from appropriate epidemiological studies from 74 countries worldwide were used to determine prevalence. In total, 180 studies were included in the analysis (90 from Europe, 41 from America and the Caribbean, 15 from Africa, 25 from Asia, 8 from Australia, and 1 from New Zealand) with a total of 191,953 participants (82,118 from America and the Caribbean, 76,612 from Europe, 21,353 from Asia, 6839 from Australia and New Zealand, and 5031 from Africa). The average smoking rate was 22.9% in Europe, 21.4% in Asia, 15.2% in both America and Africa, and 14.8% in Australia and New Zealand.

Findings

The average prevalence of MZ allele carriage among study participants was 1:32 in Australia and New Zealand, 1:58 in Europe, and 1:91 in America, with values varying significantly between countries and within a single continent. In Africa and Asia, it was not possible to determine the average global prevalence due to insufficient data.

The estimated total number of MZ allele carriers across continents was over 35 million individuals: 13.8 million in America, 11 million in Europe, 7.9 million in Asia, 1.5 million in Africa, and 837,000 in Australia and New Zealand.

The prevalence in selected countries formed the basis for creating a map using a geographic information system and the inverse distance interpolation method. Using this method, a very high prevalence of MZ allele carriage was established across Europe, between <1:80 and ≤1:40. Areas with very high prevalence included Central Europe, including the Czech Republic, although direct epidemiological data from our country was not available for the study.

In neighboring Austria, the prevalence of MZ allele carriage was 1:40, with a smoking rate of 35.1% and an estimated total number of MZ allele carriers of 225,000. In Germany, it was 1:53, with a smoking rate of 30.3% and an estimated total number of MZ allele carriers of 1.5 million. In Poland, it was 1:123, with a smoking rate of 28% and an estimated total number of MZ allele carriers of 310,000. The percentage of MZ allele carriers in the general population was 0.3% in Austria, 1.9% in Germany, and 0.8% in Poland. According to the created map, the estimated prevalence of MZ allele carriage in the Czech Republic is 1:40–60, with a similar smoking rate as in neighboring states.

The analysis results showed that 75% of MZ allele carriers are Caucasians living predominantly in Europe, America, Australia, and New Zealand. Another 20% of MZ allele carriers come from Asia, with the highest occurrence in the regions of the Middle East, Eastern, Southern, and Southeast Asia. The remaining 5% are inhabitants of Africa living in West and East Africa.

Conclusion and Discussion

According to the epidemiological study, the estimated prevalence of MZ allele carriers in certain parts of the population is quite impressive. Most commonly, these are Caucasians, with the estimated number of allele carriers within the total population ranging from 2% to 4%. In combination with the impact of exogenous factors, such as smoking or exposure to polluted air, MZ allele carriage may represent a significant risk factor for the development of COPD and possibly liver damage.

Prevention of lung and liver tissue damage is crucial in carriers of the MZ genotype. Detection of MZ alleles should, according to the study authors, lead to the introduction of effective preventive measures and patient education about the fact that while the genotype itself poses a low risk of lung and liver damage, it can contribute to the development of COPD or liver cirrhosis in adulthood when combined with other factors.

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Source: Martinez-González C., Blanco I., Diego I. et al. Estimated prevalence and number of PiMZ genotypes of alpha-1 antitrypsin in seventy-four countries worldwide. Int J Chron Obstruct Pulmon Dis 2021 Sep 17; 16: 2617–2630, doi: 10.2147/COPD.S327803.