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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

North, Teri-Louise and Ben-Shlomo, Yoav and Cooper, Cyrus and Deary, Ian J and Gallacher, John and Kivimaki, Mika and Kumari, Meena and Martin, Richard M and Pattie, Alison and Sayer, Avan Aihie and Starr, John M and Wong, Andrew and Kuh, Diana and Rodriguez, Santiago and Day, Ian NM (2016) '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.' Journal of Medical Genetics, 53 (4). pp. 280-288. ISSN 0022-2593

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Abstract

Background: Several 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). Methods: In 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. Results: Findings were mostly negative but lung function in SERPINA1 ( protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 zscore 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)). Conclusions: The 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 polytherapeutic approach in very short children. The notion that elastase inhibition should benefit patients with chronic obstructive pulmonary disease may also merit reevaluation. 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.

Item Type: Article
Uncontrolled Keywords: Humans; Cystic Fibrosis; Pulmonary Disease, Chronic Obstructive; Phenylketonurias; alpha 1-Antitrypsin Deficiency; alpha 1-Antitrypsin; HMGA2 Protein; Forced Expiratory Volume; Genotype; Heterozygote; Phenotype; Polymorphism, Genetic; Alleles; Europe; Female; Male
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 09 May 2016 13:52
Last Modified: 15 Jan 2022 00:27
URI: http://repository.essex.ac.uk/id/eprint/16492

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