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

Aaron Hakim; Matthew Moll; Dandi Qiao; Jiangyuan Liu; Jessica A Lasky-Su; Edwin K Silverman; Silvia Vilarinho; Z Gordon Jiang; Brian D Hobbs; Michael H Cho

doi:10.1002/hep4.1718

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

Hepatol Commun. 2021 Apr 3;5(8):1348-1361. doi: 10.1002/hep4.1718. eCollection 2021 Aug.

Authors

Aaron Hakim^{1

2

3}, Matthew Moll^{3

4}, Dandi Qiao³, Jiangyuan Liu³, Jessica A Lasky-Su³, Edwin K Silverman^{3

4}, Silvia Vilarinho^{5

6}, Z Gordon Jiang^{1

2}, Brian D Hobbs^{3

4}, Michael H Cho^{1

3

4}

Affiliations

¹ Department of MedicineBeth Israel Deaconess Medical CenterBostonMAUSA.
² Division of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterBostonMAUSA.
³ Channing Division of Network MedicineBrigham and Women's HospitalBostonMAUSA.
⁴ Division of Pulmonary and Critical Care MedicineBrigham and Women's HospitalBostonMAUSA.
⁵ Department of Internal MedicineSection of Digestive DiseasesYale School of MedicineNew HavenCTUSA.
⁶ Department of PathologyYale School of MedicineNew HavenCTUSA.

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.

Abstract

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