Pi*S and Pi*Z Alleles of SERPINA1 Gene Are Associated With Specific Variants of a BRD4‐Independent Enhancer

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.