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Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

ABSTRACT: Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361-0.7719 and OR 0.1522; 95% CI 0.02941-0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

SUBMITTER: Rabekova Z

PROVIDER: S-EPMC8509047 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Rabekova Zuzana Z Frankova Sona S Jirsa Milan M Neroldova Magdalena M Lunova Mariia M Fabian Ondrej O Kveton Martin M Varys David D Chmelova Klara K Adamkova Vera V Hubacek Jaroslav A JA Spicak Julius J Merta Dusan D Sperl Jan J

International journal of molecular sciences 20210929 19

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). Th ...[more]

PMID: 34638908

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Project description:Background & aimsAlpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known.MethodsThis was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models.ResultsWe included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation.ConclusionsThe SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis.Lay summaryThere is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation.

Project description:Alpha-1-Antitrypsin deficiency (AATD), caused by SERPINA1 mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p.Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare SERPINA1 variants (>500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss- or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit SERPINA1 mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.

Dataset Information

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Publications

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: <i>SERPINA1</i> MZ or MS Genotype Carriage Decreases the Risk.

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