The Undiagnosed Disease Burden Associated with Alpha-1 Antitrypsin Deficiency Genotypes.

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Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, 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 PI*ZZ individuals through genotyping could improve health-outcomes.We examined the frequency of PI*ZZ 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 FEV1/FVC was used to evaluate variable penetrance of PI*ZZ.Amongst 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only 9 of them (6.4%, 95%CI: 3.4%-11.7%) were diagnosed with AATD. Those with PI*ZZ 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 diagnoses (OR: 7.8, 95%CI 2.5-24.6) and a higher hazard of mortality (2.4, 95%CI: 1.2-4.6), compared to PI*MM(wildtype) (n=398 424). These associations were stronger amongst smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythemia, aneurysm, and pancreatitis. PRS and PI*ZZ were independently associated with FEV1/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).The important under-diagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.

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