6533b7d5fe1ef96bd12646ae
RESEARCH PRODUCT
Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.
Andreas TeufelThomas WeberSabina JanciauskieneKatharina SosnowskyD. ScholtenJanett FischerThomas BergMatthias C. ReichertCarolin V HeimesMarcin KrawczykAndrew McquillinMichael SoykaChristian TrautweinPavel StrnadStephan BuchPierre DeltenreMonika RidingerAlexandra FeldmanAnita PathilSebastian HinzMarcella RietschelMarkus CasperGreta BurmeisterChristian DatzChristoph SarrazinWitigo Von SchönfelsMichael NothnagelJm SchattenbergElmar AignerAli CanbayClemens SchafmayerMichael TraunerFrank LammertMuenevver DemirRenate SchmelzBence SiposMattias MandorferFalk KieferFelix BraunNorbert WodarzMartin SchlattjanSilke MarhenkeHeike BantelV WoditschMarsha Y. MorganHolger HinrichsenTobias BoettlerArndt VogelJochen HampeJohannes KluweJohann Von FeldenClaus HellerbrandFelix StickelMichael J. WayAndreas GeierKarim HameschMario BroschStefan BruecknerHans Dieter NischalkeJonas Rosendahlsubject
0301 basic medicineMalemedicine.medical_specialtyHeterozygoteCirrhosisMedizinSingle-nucleotide polymorphismDiseaseGastroenterologyPolymorphism Single NucleotideRisk Assessment03 medical and health sciences0302 clinical medicineAge DistributionLiver Cirrhosis AlcoholicNon-alcoholic Fatty Liver DiseaseInternal medicineGermanymedicinePiConfidence IntervalsOdds RatioHumansGenetic Predisposition to DiseaseRisk factorSex DistributionGenotypingLiver injurybusiness.industryGenetic Carrier ScreeningIncidenceFatty liverBiopsy NeedleGastroenterologyGenetic Variationmedicine.diseasePrognosisImmunohistochemistry030104 developmental biologyAustriaCase-Control Studiesalpha 1-Antitrypsin030211 gastroenterology & hepatologyFemalebusinessdescription
ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).ConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-08-01 | Gut |