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

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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. © 2013 Thun et al.

Figures

  • Figure 1. Manhattan plot of genome-wide -log(10) p-values for association with AAT serum level. SNPs reaching genome-wide significance are shown in green. They all belong to the SERPINA gene cluster. doi:10.1371/journal.pgen.1003585.g001
  • Table 1. The ten most strongly associated SNPs in the unconditional GWAS on AAT serum level in SAPALDIA (N = 1392).
  • Figure 2. Regional plot for the SERPINA gene cluster (93.8–94.2 Mb on chromosome 14q32.13, reference panel: NCBI build 36.3). Presented are -log(10) p-values and LD (r2) with top-ranking SNP rs2736887 (purple diamond) for all SNPs in this region. The blue line shows recombination rate. doi:10.1371/journal.pgen.1003585.g002
  • Figure 3. Manhattan plot of genome-wide -log(10) p-values for association with AAT serum level, conditional on PI S and PI Z alleles.
  • Table 2. The ten most strongly associated SNPs in the GWAS on AAT serum level, conditional on PI S and PI Z alleles in SAPALDIA (N = 1392).
  • Table 3. Minor allele effects of PI S, PI Z and rs4905179 on AAT serum levels in the Copenhagen City Heart Study.
  • Table 4. Common and low-frequent SERPINA1 SNPs and their association with AAT serum level, univariate and conditional on significantly associated SNPs (N = 5569a), in SAPALDIA.
  • Figure 4. LD plot among common and low-frequent SNPs in the SERPINA1 gene within the SAPALDIA study. Shading represent r2 values, whereas numbers represent D9 values (no number equals D9= 1). Red framed SNPs are independently associated with AAT serum levels after forward selection stepwise regression modeling. Rs17580 is the PI S variant and rs28929474 is the PI Z variant. doi:10.1371/journal.pgen.1003585.g004

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APA

Thun, G. A., Imboden, M., Ferrarotti, I., Kumar, A., Obeidat, M., Zorzetto, M., … Probst-Hensch, N. M. (2013). Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels. PLoS Genetics, 9(8). https://doi.org/10.1371/journal.pgen.1003585

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