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Background & Aims  Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at‐risk alcohol consumption are available. Moreover, patatin‐like phospholipase domain‐containing protein 3 ( PNPLA 3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross‐sectional studies. The aim of this study was to investigate the role of age at onset of at‐risk alcohol consumption and   PNPLA 3  I148M variant on alcoholic cirrhosis incidence.    Methods  A total of 384 at‐risk alcohol drinkers were retrospectively examined. The association among age at onset of at‐risk alcohol consumption,  PNPLA 3 I148M variant and cirrhosis incidence was tested.    Results  A higher incidence of alcoholic cirrhosis was observed in individuals with an older (≥24 years) compared with a younger (<24) age at onset of at‐risk alcohol consumption ( P ‐value < 0.001). Moreover,   PNPLA 3  148M allele carriers showed an increased incidence of cirrhosis ( P ‐value < 0.001). Both age at onset of at‐risk alcohol consumption and   PNPLA 3  148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18–3.50),  P ‐value < 0.001; 1.53(1.07–2.19),  P ‐value = 0.021 respectively). The 148M allele was associated with a two‐fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at‐risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53–6.00) vs. 1.61(1.09–2.38).    Conclusions  Age at onset of at‐risk alcohol consumption and   PNPLA 3  I148M genetic variant are independently associated with alcoholic cirrhosis incidence.

PNPLA3 I148M (rs738409) genetic variant and age at onset of at‐risk alcohol consumption are independent risk factors for alcoholic cirrhosis