SynthesisJournal of medical genetics2016
A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height.
Synthesis in Journal of medical genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- Dual SORT LNPs for multi-organ base editing.Nature biotechnology · 2026Article
- Alpha1-Antitrypsin in Lung Diseases: A Cross-Sectional Observational Study.International journal of molecular sciences · 2025Observational
- Genetics of chronic respiratory disease.Nature reviews. Genetics · 2024Review
- Pleiotropic associations of heterozygosity for theERJ open research · 2021Article
- Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview ofThe application of clinical genetics · 2021Review
- Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations.Scientific reports · 2017Article
- The comparison of the performance of four whole genome amplification kits on ion proton platform in copy number variation detection.Bioscience reports · 2017Article
- Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.American journal of human genetics · 2017Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 1 country.
Funding
Abstract
backgroundSeveral recessive Mendelian disorders are common in Europeans, including cystic fibrosis (CFTR), medium-chain-acyl-Co-A-dehydrogenase deficiency (ACADM), phenylketonuria (PAH) and alpha 1-antitrypsin deficiency (SERPINA1).
methodsIn a multicohort study of >19,000 older individuals, we investigated the relevant phenotypes in heterozygotes for these genes: lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) for CFTR and SERPINA1; cognitive measures for ACADM and PAH; and physical capability for ACADM, PAH and SERPINA1.
resultsFindings were mostly negative but lung function in SERPINA1 (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 z-score increase in FEV1 (p=1.7 × 10(-5)) and 0.16 z-score increase in FVC (p=5.2 × 10(-8))) in PI-MZ individuals. Height adjustment (a known, strong correlate of FEV1 and FVC) revealed strong positive height associations of the Z allele (1.50 cm increase in height (p=3.6 × 10(-10))).
conclusionsThe PI-MZ rare (2%) SNP effect is nearly four times greater than the 'top' common height SNP in HMGA2. However, height only partially attenuates the SERPINA1-FEV1 or FVC association (around 50%) and vice versa. Height SNP variants have recently been shown to be positively selected collectively in North versus South Europeans, while the Z allele high frequency is localised to North Europe. Although PI-ZZ is clinically disadvantageous to lung function, PI-MZ increases both height and respiratory function; potentially a balanced polymorphism. Partial blockade of PI could conceivably form part of a future poly-therapeutic approach in very short children. The notion that elastase inhibition should benefit patients with chronic obstructive pulmonary disease may also merit re-evaluation. PI is already a therapeutic target: our findings invite a reconsideration of the optimum level in respiratory care and novel pathway potential for development of agents for the management of growth disorders.
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