ArticlePLoS genetics2013
Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 3 of them syntheses that pooled it.
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Who cites it
28 citing papers in PubMed, 3 syntheses or guidelines pooled it, 61 citations in OpenAlex.
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- Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.American journal of respiratory cell and molecular biology · 2017Pooled it
- Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.PLoS genetics · 2016Pooled it
- Pulmonary-Intestinal Axis: Shared Genetic Basis and Mediating Factors Identified Through Multi-Omics Analysis.International journal of chronic obstructive pulmonary disease · 2026Article
- αThe journal of allergy and clinical immunology. In practice · 2025Article
- The Genetics behind Sulfation: Impact on Airway Remodeling.Journal of personalized medicine · 2024Review
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- Single-nucleotide polymorphisms in the sulfatase-modifying factor 1 gene are associated with lung function and COPD.ERJ open research · 2022Article
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- The Effects of RareAmerican journal of respiratory and critical care medicine · 2020Article
- Genetic underpinnings of lung function and COPD.Journal of genetics · 2019Review
- Benefits and limitations of genome-wide association studies.Nature reviews. Genetics · 2019Review
- Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.American journal of respiratory cell and molecular biology · 2018Article
- SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts.Respiratory research · 2018Article
- Genome-wide association study of lung function and clinical implication in heavy smokers.BMC medical genetics · 2018Article
- Attenuating immune pathology using a microbial-based intervention in a mouse model of cigarette smoke-induced lung inflammation.Respiratory research · 2017Article
- Common coding variant inProceedings of the National Academy of Sciences of the United States of America · 2017Article
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- Interactions between single nucleotide polymorphism ofInternational journal of chronic obstructive pulmonary disease · 2017Article
- Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach.Oncotarget · 2016Article
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43 authors at 20 institutions in 13 countries.
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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.
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