A consortium involving researchers from six countries has published two studies that identify risk factors associated with alcohol-related cirrhosis, the University of Liverpool reports. The GenomALC Consortium was established more than 10 years ago to determine why some people who drink heavily go on to develop cirrhosis and others do not.
Alcohol-related cirrhosis is the scarring of liver tissue caused by alcohol consumption.
The researchers, including Professor Sir Munir Pirmohamed and Dr Andrew Thompson from the University of Liverpool, conducted two studies recruiting patients diagnosed with alcohol-related cirrhosis and compared them to individuals with a similar drinking history but no evidence of liver damage.
First study
According to University of Liverpool material published on 9 October 2020, the first study looked at risk factors such as drinking patterns, preferred type of alcoholic drink and other non-alcohol lifestyle choices that are associated with cirrhosis.
The findings showed that diabetes and increased BMI as a young adult were more common in patients with cirrhosis. There was also evidence that people without liver damage were more likely to have been wine drinkers, coffee drinkers, smokers and cannabis users.
Second study
The second study used a genome-wide association study, GWAS, to pinpoint the genes responsible for increasing the risk of cirrhosis. This method searches a person’s DNA (genome) for small variations, called single nucleotide polymorphisms or SNPs.
Each person carries many millions of SNPs, but if a particular SNP occurs more frequently in people with a particular condition than in people without the condition, it can suggest the underlying reason for the difference.
A new genetic association between the gene FAF2 and alcohol-related cirrhosis was reported. This gene is involved with lipid fat metabolism in liver cells, which may explain its involvement in increasing the risk of cirrhosis.
Improving understanding
The findings from both studies were found to be consistent in a second cohort from the UK Biobank, helping to confirm the validity of the results.
Professor Sir Munir Pirmohamed said: “The results of both these studies help us improve our understanding of this terrible and serious type of liver disease. These genetic and non-genetic risk factors provide new knowledge into why some people might be vulnerable to cirrhosis.”
According to Dr Andrew Thompson: “Improving our understanding of the factors leading to alcohol-related liver cirrhosis presents new opportunities for risk stratification and developing treatment options.”
Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers
The American Journal of Gastroenterology. Published on 31 August 2020.
Authors
John Whitfield, Steven Masson, Suthat Liangpunsakul, Sebastian Mueller, Guruprasad Aithal, Florian Eyer, Dermot Gleeson, Andrew Thompson, Felix Stickel, Michael Soyka, Ann K Daly, Heather Cordell, Tatiana Foroud, Lawrence Lumeng, Munir Pirmohamed, Bertrand Nalpas, Jean-Marc Jacquet, Romain Moirand, Pierre Nahon, Sylvie Naveau, Pascal Perney, Paul S Haber, Helmut K Seitz, Christopher P Day, Philippe Mathurin, Timothy Morgan, Devanshi Seth and the The GenomALC Consortium.
Abstract
Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk.
Methods
We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male).
Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank.
Results
The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10−18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10−15).
Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55–3.26).
Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption.
Discussion
If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.
Genome‐wide association study and meta‐analysis on alcohol‐related liver cirrhosis identifies novel genetic risk factors
Hepatology journal. Published on 27 August 2020.
Authors
Tae-Hwi Schwantes-An, Rebecca Darlay, Philippe Mathurin, Steven Masson, Suthat Liangpunsakul, Sebastian Mueller, Guruprasad P Aithal, Florian Eyer, Dermot Gleeson, Andrew Thompson, Beat Muellhaupt, Felix Stickel, Michael Soyka, David Goldman, Tiebing Liang, Lawrence Lumeng, Munir Pirmohamed, Bertrand Nalpas, Jean-Marc Jacquet, Romain Moirand, Pierre Nahon, Sylvie Naveau, Pascal Perney, Greg Botwin, Paul S Haber, Helmut K Seitz, Christopher P Day, Tatiana M Foroud, Ann K Daly, Heather J Cordell, John B Whitfield, Timothy R Morgan, Devanshi Seth and The GenomALC Consortium.
Abstract
Only a minority of heavy drinkers progress to alcohol‐related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. We analysed data from 1,128 subjects of European ancestry with ALC and 614 heavy drinking subjects without known liver disease from Australia, the United States, the United Kingdom and three countries in Europe.
Genome‐wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta‐analysis combining data from our study, the UK Biobank, and a previously published GWAS.
Our GWAS found genome‐wide significant risk association of rs738409 in PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p‐value=4.93×10‐17) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p‐value=1.09×10‐10) with ALC.
Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p‐value=2.56×10‐8) for ALC.
This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p‐value=0.001). Meta‐analysis (without conditioning) confirmed genome‐wide significance for the newly identified FAF2 locus as well as PNPLA3and HSD17B13.
Two other previously known loci (SERPINA1, SUGP1/TM6SF2) were also genome‐wide significant in the meta‐analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a new locus at FAF2 associated with reduced risk of ALC among heavy drinkers.
Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
[link url="https://news.liverpool.ac.uk/2020/10/09/new-studies-identify-risk-factors-associated-with-alcohol-related-cirrhosis/”]New studies identify risk factors associated with alcohol-related cirrhosis[/link]
[link url="https://journals.lww.com/ajg/Abstract/9000/Obesity,_Diabetes,_Coffee,_Tea,_and_Cannabis_Use.99148.aspx”]Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers[/link]
[link url="https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.31535”]Genome‐wide association study and meta‐analysis on alcohol‐related liver cirrhosis identifies novel genetic risk factors[/link]