Hyun-Seok Kim1, Xiangjun Xiao2, Jinyoung Byun2, Goo Jun3, Stacia M DeSantis4, Han Chen3, Aaron P Thrift2,5, Hashem B El-Serag6,7, Fasiha Kanwal6,7, Christopher I Amos2,5,8. 1. Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. 2. Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas. 3. Department of Epidemiology, Human Genetics & Environmental Sciences and Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston. 4. Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston. 5. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. 6. Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas. 7. Clinical Epidemiology and Comparative Effectiveness Program, Section of Health Services Research, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. 8. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas.
Abstract
Importance: Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. Objective: To investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality. Design, Setting, and Participants: This prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021. Exposures: Self-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment. Main Outcomes and Measures: The primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models. Results: A total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity. Conclusions and Relevance: This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.
Importance: Alcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk. Objective: To investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality. Design, Setting, and Participants: This prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021. Exposures: Self-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment. Main Outcomes and Measures: The primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models. Results: A total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity. Conclusions and Relevance: This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.
Authors: M Graff; K E North; N Franceschini; A P Reiner; M Feitosa; J J Carr; P Gordon-Larsen; M K Wojczynski; I B Borecki Journal: Int J Obes (Lond) Date: 2012-05-01 Impact factor: 5.095
Authors: Stefano Romeo; Julia Kozlitina; Chao Xing; Alexander Pertsemlidis; David Cox; Len A Pennacchio; Eric Boerwinkle; Jonathan C Cohen; Helen H Hobbs Journal: Nat Genet Date: 2008-09-25 Impact factor: 38.330
Authors: Stefan Stender; Julia Kozlitina; Børge G Nordestgaard; Anne Tybjærg-Hansen; Helen H Hobbs; Jonathan C Cohen Journal: Nat Genet Date: 2017-04-24 Impact factor: 38.330