English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

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.

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