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

Abstract

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 (PNPLA3) 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 PNPLA3 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, PNPLA3 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, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 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 PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.

Keywords: Age at onset; alcohol intake; alcoholic liver disease; genetics; incidence; patatin-like phospholipase domain-containing protein 3; polymorphism.

Figure 1

Cumulative incidence of alcoholic cirrhosis in individuals stratified by age at onset of at-risk alcohol consumption. Individuals were stratified by the median value of the age at onset of at-risk alcohol consumption, which was equal to 24 years. FU indicates the duration (years) of at-risk alcohol consumption, which was defined as a daily intake of ≥3 and ≥2 alcohol units for men and women respectively. Number of events: <24 Years, n = 25; ≥24 Years, n = 59. The number at the bottom indicates the number of individuals at risk at the following time points: 0, 10, 20, 30 and 40 years. Abbreviations: FU, follow-up.

Figure 2

Cumulative incidence of alcoholic cirrhosis in individuals according to PNPLA3 I148M genotype. Individuals were stratified by the PNPLA3 I148M genotype. FU indicates the duration (years) of at-risk alcohol consumption, which was defined as a daily intake of ≥3 and ≥2 alcohol units for men and women respectively. Number of events: II, n = 19; IM, n = 39; MM, n = 26. The number at the bottom indicates the number of individuals at risk at the following time point: 0, 10, 20, 30 and 40 years. Abbreviations: PNPLA3, patatin-like phospholipase domain-containing 3; II, individuals with two 148I alleles; MM, individuals with two 148M alleles; IM, heterozygotes; FU, follow-up.

Figure 3

Cumulative incidence of alcoholic cirrhosis in individuals stratified by age at onset of at-risk alcohol consumption and PNPLA3 I148M genotype. Individuals were stratified by the median value of the age at onset of at-risk alcohol consumption, which was equal to 24 years, into two groups. Next, each group was divided according to the PNPLA3 I148M genotype. FU indicates the duration (years) of at-risk alcohol consumption, which was defined as a daily intake of ≥3 and ≥2 alcohol units for men and women respectively. The number of events was as follows: II n = 4, IM n = 13, MM n = 8 (<24 Years); II n = 15, IM n = 26, MM n = 18 (≥24 Years). The number at the bottom indicates the number of individuals at risk at the following time points: 0, 10, 20, 30 and 40 years. Abbreviations: PNPLA3, patatin-like phospholipase domain-containing 3; II, individuals with two 148I alleles; MM, individuals with two 148M alleles; IM, heterozygotes; FU, follow-up.