The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes.

Alpha-1 antitrypsin deficiency (AATD), mainly due to the PIZZ genotype in , is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PIZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PIZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PIZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PIZZ genotype and only nine (6.4%, 95% CI 3.4-11.7%) of them were diagnosed with AATD. Those with PIZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8-13.3), asthma (OR 2.0, 95% CI 1.4-3.0), bronchiectasis (OR 7.3, 95%CI 3.2-16.8), pneumonia (OR 2.7, 95% CI 1.5-4.9) and cirrhosis (OR 7.8, 95% CI 2.5-24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2-4.6), compared to PIMM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PIZZ were independently associated with FEV/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4-1.5 and OR 4.5, 95% CI 3.0-6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.