Original research: Amplification of genetic and metabolic factors in alpha-1 antitrypsin deficiency.

Background And Aims Severe (Pi*ZZ) and heterozygous (Pi*MZ) alpha-1 antitrypsin deficiency (AATD) confer increased liver- and lung-related mortality, but the phenotype is highly variable. We aimed to evaluate the impact of obesity and diabetes mellitus on individuals with/without AATD. Approach And Results Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. 983 participants had a longitudinal follow-up. The data were compared to 16,768 Pi*MZ and 415,208 non-AATD individuals from the United Kingdom Biobank (cohort 2). Findings were ascertained by multivariable adjustment and propensity score matching. At baseline, diabetes was present in 52 (3%), overweight (BMI 25.0-29.9 kg/m2) in 540 (52%) and obesity (BMI≥30 kg/m2) in 266 (32%) Pi*ZZ adults. Pi*ZZ individuals with diabetes showed higher transaminases and surrogates of advanced liver fibrosis (APRI≥1.0, LSM≥15 kPa) were four to six times more common (adjusted Odds Ratio (aOR) 5.7/4.3, p<0.01). Elevated transaminases were rare among lean Pi*ZZ subjects, but more common in overweight (aOR 1.5/2.0) and obese Pi*ZZ participants (aOR 2.1/2.9). APRI≥1.0 was more than four times elevated in obese vs. lean Pi*ZZ individuals (aOR 4.1, p<0.001). During a median follow-up of 4.2 years, 54 Pi*ZZ participants experienced a hepatic and 64 a pulmonary endpoint. While Pi*ZZ participants with diabetes/obesity had an increased risk of hepatic endpoints (aHR 6.03/3.38, p<0.001) compared with non-diabetic/lean Pi*ZZ subjects, overweight was associated with a decreased risk of pulmonary endpoints (aHR 0.45, p=0.004). Conclusions Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.