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

<jats:sec> <jats:title>Background</jats:title> <jats:p>Several recessive Mendelian disorders are common in Europeans, including cystic fibrosis (<jats:italic>CFTR</jats:italic>), medium-chain-acyl-Co-A-dehydrogenase deficiency (<jats:italic>ACADM</jats:italic>), phenylketonuria (<jats:italic>PAH</jats:italic>) and alpha 1-antitrypsin deficiency (<jats:italic>SERPINA1</jats:italic>).</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>In a multicohort study of &gt;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 <jats:italic>CFTR</jats:italic> and <jats:italic>SERPINA1</jats:italic>; cognitive measures for <jats:italic>ACADM</jats:italic> and <jats:italic>PAH</jats:italic>; and physical capability for <jats:italic>ACADM</jats:italic>, <jats:italic>PAH</jats:italic> and <jats:italic>SERPINA1</jats:italic>.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Findings were mostly negative but lung function in <jats:italic>SERPINA1</jats:italic> (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.13 z-score increase in FEV1 (p=1.7×10<jats:sup>−5</jats:sup>) and 0.16 z-score increase in FVC (p=5.2×10<jats:sup>−8</jats:sup>)) 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<jats:sup>−10</jats:sup>)).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>The PI-MZ rare (2%) SNP effect is nearly four times greater than the ‘top’ common height SNP in <jats:italic>HMGA2</jats:italic>. However, height only partially attenuates the <jats:italic>SERPINA1-</jats:italic>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.</jats:p> </jats:sec>