title: 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.
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Teri-Louise
authors.initials: TL
authors.lastname: North
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Ben-Shlomo
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK National Institute for Health Research Nutrition Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK National Institute for Health Research Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Gallacher
authors.affiliation: Department of Epidemiology and Public Health, UCL, London, UK.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.affiliation: Department of Epidemiology and Public Health, UCL, London, UK ISER, University of Essex, Essex, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK University of Bristol/University Hospitals Bristol NHS Foundation Trust National Institute for Health Research Bristol Nutrition Biomedical Research Unit, University of Bristol, Bristol, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
authors.affiliation: Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Pattie
authors.affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
authors.forename: Avan Aihie
authors.initials: AA
authors.lastname: Sayer
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.affiliation: MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuh
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D000483:Alleles; D003550:Cystic Fibrosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005060:Europe; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D005838:Genotype; D025743:HMGA2 Protein / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D010641:Phenotype; D010661:Phenylketonurias / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D025743:HMGA2 Protein; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: ALSPAC; Alpha 1-Antitrypsin; HALCion; Mendelian carriers; height
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