# Pi∗S and Pi∗Z Alleles of SERPINA1 Gene Are Associated With Specific Variants of a BRD4-Independent Enhancer

## TL;DR

This study finds that specific variants in the SERPINA1 gene are linked to certain enhancer alleles, which may influence alpha-1 antitrypsin deficiency.

## Contribution

The study identifies novel associations between SERPINA1 Pi∗S and Pi∗Z alleles and specific SERPINA-BIE enhancer alleles.

## Key findings

- Pi∗Z allele is associated with SERPINA-BIE allele 13 (p = 5.51 × 10−10).
- Pi∗S allele is associated with SERPINA-BIE allele 14 (p = 8.95 × 10−15).
- SERPINA-BIE alleles do not affect AAT levels when corrected for SERPINA1 genotypes.

## Abstract

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by specific variants in the SERPINA1 gene, which encodes AAT. The most common disease-associated SERPINA1 variants are Pi∗S and Pi∗Z alleles, which cause moderate and severe AATD, respectively. Recent studies have reported the presence of a possible regulator of SERPINA gene cluster expression (LOC126862032), which is suggested to act as a BRD4-Independent Enhancer (SERPINA-BIE). This study is aimed at characterizing the SERPINA-BIE locus and assessing possible associations with SERPINA1 AATD-related alleles. For this purpose, SERPINA-BIE was PCR genotyped from 917 samples, including 452 asthmatic patients, and 465 newborns. Nine SERPINA-BIE alleles were sequenced, revealing a specific combination of 56-bp sequence types, and each SERPINA-BIE allele has a unique total number of CpG sites. Statistical analyses revealed an association between the Pi∗Z allele of the SERPINA1 gene and the SERPINA-BIE allele 13 (p value = 5.51 × 10−10), as well as between Pi∗S and SERPINA-BIE allele 14 (p value = 8.95 × 10−15). However, AAT levels were not associated with SERPINA-BIE alleles when models were corrected by SERPINA1 genotypes. This study could contribute to a better understanding of the regulation of the SERPINA1 gene expression, and its role in AATD.