Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Abstract

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

“…Thus, heterozygous carriers of the Z allele appear to be driving a large proportion of the association, consistent with prior studies showing an increased risk of COPD for MZ heterozygotes (48). In addition, these results suggest that if we had not specifically excluded subjects with known alpha-1 antitrypsin deficiency in our other populations, the association with SNP rs112458284 would likely be even more extreme (49). Allele frequencies for the Z allele in each cohort are provided in Table E3.…”

Common coding variant in SERPINA1 increases the risk for large artery stroke

“…Second, we found no differences in the frequency of the Z and S alleles between cases and controls. Third, the association between rs6647 and LAS remained stable when removing carriers of a Z or S allele from our cohorts (35). Finally, eQTL analysis in the Athero-Express data showed no eQTL of M1 (A213).…”

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

“…According to a recent genome-wide association study, most of the reduced a1PI levels in plasma are explained by specific germline mutations leading to the S and Z variants but do not accurately predict the degree of deterioration of long-term lung function (Thun et al 2013). Other factors, such as inflammatory mediators and the tissue-specific regulation of a1PI, may play a role in lung disease among individuals with a1PI deficiency.…”