Approved research

Analysis of Alpha1-Antitrypsin related comorbidities

Lay summary

Severe Alpha1-antitrypsin deficiency (AATD) is the third most common genetic disorder leading to death and is caused mainly by the homozygous PiZ mutation (termed as Pi*ZZ). While lung and disease constitute the leading causes of AATD-related mortality, multiple other disorders including panniculitis and vasculitis have been described to associate with AATD. While the Pi*ZZ genotype is relatively rare,the heterozygous carriage of PiZ allele (termed Pi*MZ) is seen in ~2% of European population, however the health risks associated with this genotype remain unknown. Recently, we demonstrated that PiZ carriage predisposes alcohol misusers as well as individuals with non-alcoholic fatty liver disease to development of liver cirrhosis. As the next step, we want to characterize the health risks associated with the Pi*MZ in the general population. For this purpose, we would like to use the UK biobank and compare a variety of metabolic and organ-related parameters between PiZ carriers and non-carriers. The parameters, that will display significant differences between the groups, will be subjected to multivariate analysis to account for confounders.

Scope extension:

The aim of our study is to characterize the disease phenotype in patients with heterozygous alpha1-antitrypsin deficiency (Pi*MZ).  

Homozygous carriers of the alpha1-antitrypsin (AAT) 'Pi*Z' variant (Pi*ZZ genotype) are susceptible to develop liver cirrhosis, whereas the heterozygous Pi*Z carriage (Pi*MZ genotype) acts as a disease modifier in patients with alcohol abuse or non-alcoholic fatty liver disease. Until now, the hepatic relevance of Pi*MZ in subjects in the absence of another etiology of chronic liver disease remains unknown. To change that, we recruited a multi-center cohort of 255 Pi*MZ patients. Based on our unpublished data, serum liver enzymes of those Pi*MZ patients differed significantly from Pi*MM and Pi*ZZ patients. Moreover, differences in other serum parameters including lipid parameters were also observed. This is not surprising, since AAT constitutes an important anti-protease as well as an immunomodulatory protein and its mutations have been associated with multiple disorders such as panniculitis or vasculitis. Therefore, the goal of this study will be to validate these findings and potentially discover new comorbidities of Pi*MZ individuals. For this, the population-based cohort available in the UK Biobank represents a unique resource and excludes selection bias that might be seen in smaller settings.

While analyzing the phenotype of Pi*MZ individuals (for first results, see Schneider et al., Gastroenterology in press), we recognized, how powerful the UK biobank is. Because of that, we decided to extend our analyses to other AAT deficiency genotypes available in the UK biobank. In addition, we would like to use UK biobank to study to consequences of common digestive disorders as well as their potential genetic modifiers. We are particularly interested in the "gut-liver axis", i.e. to understand the impact of chronic intestinal disorders on the liver. Given our strong interest in the liver, we also would like to study demographic and biochemical parameters, that are associated with the increased risk of liver-related death.

Our current aim is to use the UK Biobank to study the consequences of common digestive disorders as well as their potential genetic modifiers. We are particularly interested in the "gut-liver axis", i.e. to understand the impact of chronic intestinal disorders on the liver. Given our strong interest in the liver, we also study demographic and biochemical parameters, that are associated with the increased risk of liver-related death.

During our analyses, we noted the strong association of leukocyte telomere length (LTL) with digestive diseases, particularly with liver diseases. This is of great interest for us, since it extends our earlier findings demonstrating that mutations in the telomerase gene predispose to the development of liver cirrhosis. However, since LTL is a general marker of organismal telomere length, a real understanding of this topic can be only reached when adjusting for multiple factors and when comparing the situation in the liver with processes occurring in other organs.

As we started our research regarding chronic digestive disorders, which are associated with alpha1-antitrypsin deficiency, we found that lichen planus was a common comorbidity. Therefore, we want go explore the effects of lichen planus on other digestive diseases and other dermatological disorders.