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

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 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))).

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 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.

Keywords: ALSPAC; Alpha 1-Antitrypsin; HALCion; Mendelian carriers; height.

Figure 1

Regression coefficients from fixed effects one-step meta-analysis of protease inhibitor-MZ effect on lung function (z-scored within cohorts) adjusted for age and sex. Estimates from analyses stratified by smoking status are also provided (current smokers N=2430; ex smokers N=6422; never smokers N=5473). FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Figure 2

The pleiotropic effect of the Z allele on respiratory capacity and height. ‘Unadjusted’ estimates are from the (upper circle) one-step fixed effects analyses of z-scored forced expiratory volume in 1 second (FEV1) or z-scored forced vital capacity (FVC) on protease inhibitor (PI)-MZ versus PI-MM adjusted for age and sex or (lower circle) from the one-step fixed effects analysis of height (cm) on PI-MZ versus PI-MM adjusted for age and sex. The ‘adjusted’ estimates are additionally adjusted for (upper circle) height (cm) and (lower circle) z-scored FEV1 and z-scored FVC simultaneously.