RT Journal Article SR Electronic T1 Pleiotropic associations of heterozygosity for the SERPINA1 Z allele in the UK Biobank JF ERJ Open Research JO erjor FD European Respiratory Society SP 00049-2021 DO 10.1183/23120541.00049-2021 A1 Katherine A. Fawcett A1 Kijoung Song A1 Guoqing Qian A1 Aliki-Eleni Farmaki A1 Richard Packer A1 Catherine John A1 Nick Shrine A1 Raquel Granell A1 Sue Ring A1 Nicholas J. Timpson A1 Laura M. Yerges-Armstrong A1 Richard Eastell A1 Louise V. Wain A1 Robert A. Scott A1 Martin D. Tobin A1 Ian P. Hall YR 2021 UL http://openres.ersjournals.com/content/early/2021/02/25/23120541.00049-2021.abstract AB Homozygosity for the SERPINA1 Z allele causes alpha-1 antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on non-respiratory phenotypes, and on lung function in the general population, remain unclear.We conducted a large population-based study to determine Z allele effects on >2400 phenotypes in UK Biobank (N>303 353).Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other non-respiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (FEV1/FVC) (β=0.0031, p=1.22×10−5) in non-smokers, whereas in smokers this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function.We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with non-respiratory health-related traits and disease risk.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of Interest: Dr. Fawcett reports grants from Asthma UK, outside the submitted work.Conflict of Interest: Dr. Song has nothing to disclose.Conflict of Interest: Dr. Qian has nothing to disclose.Conflict of Interest: Dr. Farmaki has nothing to disclose.Conflict of Interest: Dr. Packer reports grants from Orion Pharma, outside the submitted work.Conflict of Interest: Dr. John reports grants from Medical Research Council, during the conduct of the study.Conflict of Interest: Dr. Shrine has nothing to disclose.Conflict of Interest: Dr. Granell has nothing to disclose.Conflict of Interest: Dr. Ring has nothing to disclose.Conflict of Interest: Dr. Timpson has nothing to disclose.Conflict of Interest: Dr. Yerges-Armstrong is an employee/stockholder of GlaxoSmithKline.Conflict of Interest: Dr. Eastell reports grants from Amgen, grants and personal fees from IDS, grants from Alexion, grants and personal fees from Roche, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from AbbVie, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from FNIH, personal fees from Viking, personal fees from UCSF, personal fees from Biocon, from Lyramid, outside the submitted work.Conflict of Interest: Dr. Wain reports grants from GSK, outside the submitted work.Conflict of Interest: R.A. Scott is an employee and shareholder of GSK.Conflict of Interest: Dr. Tobin reports grants from GSK, grants from Orion Pharma, outside the submitted work.Conflict of Interest: Dr. Hall reports grants from GSK, grants from Boehringer Ingelheim, grants from Orion, outside the submitted work.