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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

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  • Teri-Louise North
  • Yoav Ben-Shlomo
  • Cyrus Cooper
  • Ian J Deary
  • John Gallacher
  • Mika Kivimaki
  • Meena Kumari
  • Richard M Martin
  • Alison Pattie
  • Avan Aihie Sayer
  • John M Starr
  • Andrew Wong
  • Diana Kuh
  • Santiago Rodriguez
  • Ian N M Day

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Original languageEnglish
JournalJournal of Medical Genetics
Early online date1 Feb 2016
Publication statusE-pub ahead of print - 1 Feb 2016


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.

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