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Heterozygosity of the Alpha 1-Antitrypsin Pi*Z Allele and Risk of Liver Disease.

ABSTRACT: The serpin family A member 1 (SERPINA1) Z allele is present in approximately one in 25 individuals of European ancestry. Z allele homozygosity (Pi*ZZ) is the most common cause of alpha 1-antitrypsin deficiency and is a proven risk factor for cirrhosis. We examined whether heterozygous Z allele (Pi*Z) carriers in United Kingdom (UK) Biobank, a population-based cohort, are at increased risk of liver disease. We replicated findings in Massachusetts General Brigham Biobank, a hospital-based cohort. We also examined variants associated with liver disease and assessed for gene-gene and gene-environment interactions. In UK Biobank, we identified 1,493 cases of cirrhosis, 12,603 Z allele heterozygotes, and 129 Z allele homozygotes among 312,671 unrelated white British participants. Heterozygous carriage of the Z allele was associated with cirrhosis compared to noncarriage (odds ratio [OR], 1.53; P = 1.1×10^-04); homozygosity of the Z allele also increased the risk of cirrhosis (OR, 11.8; P = 1.8 × 10^-09). The OR for cirrhosis of the Z allele was comparable to that of well-established genetic variants, including patatin-like phospholipase domain containing 3 (PNPLA3) I148M (OR, 1.48; P = 1.1 × 10^-22) and transmembrane 6 superfamily member 2 (TM6SF2) E167K (OR, 1.34; P = 2.6 × 10^-06). In heterozygotes compared to noncarriers, the Z allele was associated with higher alanine aminotransferase (ALT; P = = 4.6 × 10^-46), aspartate aminotransferase (AST; P = 2.2 × 10^-27), alkaline phosphatase (P = 3.3 × 10^-43), gamma-glutamyltransferase (P = 1.2 × 10^-05), and total bilirubin (P = 6.4 × 10^-06); Z allele homozygotes had even greater elevations in liver biochemistries. Body mass index (BMI) amplified the association of the Z allele for ALT (P interaction = 0.021) and AST (P interaction = 0.0040), suggesting a gene-environment interaction. Finally, we demonstrated genetic interactions between variants in PNPLA3, TM6SF2, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13); there was no evidence of epistasis between the Z allele and these variants. Conclusion: SERPINA1 Z allele heterozygosity is an important risk factor for liver disease; this risk is amplified by increasing BMI.

SUBMITTER: Hakim A

PROVIDER: S-EPMC8369947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsAlpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi∗Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi∗Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion.MethodsA total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi∗Z/Pi∗S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks.ResultsViral hepatitis was the most common etiology (44%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi∗Z and Pi∗S variants, respectively. Pi∗Z carriers had more severe portal hypertension (HVPG: 19±6 vs.15±7 mmHg; p <0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1±1.9 vs. 6.5±1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi∗S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi∗Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi∗MZ genotype (adjusted subdistribution hazard ratio: ≈1.56 vs. Pi∗MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi∗S carriers had no increased risk of events.ConclusionGenotyping for the Pi∗Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease-modifying treatments in Pi∗Z allele carriers with ACLD.Lay summaryAlpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect.

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Heterozygosity of the Alpha 1-Antitrypsin Pi*Z Allele and Risk of Liver Disease.

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