Browsing by Author "Mathurin, Philippe"
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Item A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers(Elsevier, 2022) Whitfield, John B.; Schwantes-An, Tae-Hwi; Darlay, Rebecca; Aithal, Guruprasad P.; Atkinson, Stephen R.; Bataller, Ramon; Botwin, Greg; Chalasani, Naga P.; Cordell, Heather J.; Daly, Ann K.; Day, Christopher P.; Eyer, Florian; Foroud, Tatiana; Gleeson, Dermot; Goldman, David; Haber, Paul S.; Jacquet, Jean-Marc; Liang, Tiebing; Liangpunsakul, Suthat; Masson, Steven; Mathurin, Philippe; Moirand, Romain; McQuillin, Andrew; Moreno, Christophe; Morgan, Marsha Y.; Mueller, Sebastian; Müllhaupt, Beat; Nagy, Laura E.; Nahon, Pierre; Nalpas, Bertrand; Naveau, Sylvie; Perney, Pascal; Pirmohamed, Munir; Seitz, Helmut K.; Soyka, Michael; Stickel, Felix; Thompson, Andrew; Thursz, Mark R.; Trépo, Eric; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medical and Molecular Genetics, School of MedicineBackground & aims: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. Methods: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). Results: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. Conclusions: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. Lay summary: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.Item A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry(Wolters Kluwer, 2024-05-10) Schwantes-An, Tae-Hwi; Whitfield, John B.; Aithal, Guruprasad P.; Atkinson, Stephen R.; Bataller, Ramon; Botwin, Greg; Chalasani, Naga P.; Cordell, Heather J.; Daly, Ann K.; Darlay, Rebecca; Day, Christopher P.; Eyer, Florian; Foroud, Tatiana; Gawrieh, Samer; Gleeson, Dermot; Goldman, David; Haber, Paul S.; Jacquet, Jean-Marc; Lammert, Craig S.; Liang, Tiebing; Liangpunsakul, Suthat; Masson, Steven; Mathurin, Philippe; Moirand, Romain; McQuillin, Andrew; Moreno, Christophe; Morgan, Marsha Y.; Mueller, Sebastian; Müllhaupt, Beat; Nagy, Laura E.; Nahon, Pierre; Nalpas, Bertrand; Naveau, Sylvie; Perney, Pascal; Pirmohamed, Munir; Seitz, Helmut K.; Soyka, Michael; Stickel, Felix; Thompson, Andrew; Thursz, Mark R.; Trépo, Eric; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medical and Molecular Genetics, School of MedicineBackground: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. Methods: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). Results: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. Conclusions: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.Item Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Chalasani, Naga P.; Anstee, Quentin M.; Kowdley, Kris V.; George, Jacob; Goodman, Zachary D.; Lindor, Keith; Medicine, School of MedicineNASH/NAFLD is rapidly becoming one of top causes of cirrhosis, hepatocellular carcinoma and indication for liver transplantation. Except for life style modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is hard to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD and has been shown to improve liver histology. In order to have approved regimens for treatment of NASH/NAFLD, a number of issues that must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced stage of fibrosis, it is not an independent predictor of long term mortality. In contrast, there is significant data to suggest that stage of fibrosis is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, a number of important secondary endpoints, including non-invasive biomarkers, long term outcomes, and patient reported outcomes, must be considered. In 2017, a few phase 3 clinical trials for treatment of NASH are in progress. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH enriches the pipeline of emerging therapies. Conclusion: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD.Item Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Anstee, Quentin M.; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Goodman, Zachary D.; Chalasani, Naga P.; Kowdley, Kris V.; George, Jacob; Lindor, Keith; Medicine, School of MedicineNAFLD is a spectrum comprised of isolated steatosis, NASH, advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and don't carry a significant risk for adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high prevalence rates to low rates are noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition as an important liver disease, the diagnosis of NASH still requires a liver biopsy which is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, it suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathologic features. A number of non-invasive modalities to diagnose NASH and stage liver fibrosis are being developed. These include predictive models (NAFLD fibrosis score) and serum biomarkers such as Enhanced Liver Fibrosis, (ELF). Other tests are based on radiologic techniques such as transient or MR elastography (MRE) which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have AUROC between 0.76 to 0.90% with MRE having the best predictive performance. In summary, developing accurate, safe and easily accessible non-invasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease but to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH.Item Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors(Wiley, 2021-05) Schwantes-An, Tae-Hwi; Darlay, Rebecca; Mathurin, Philippe; Masson, Steven; Liangpunsakul, Suthat; Mueller, Sebastian; Aithal, Guruprasad P.; Eyer, Florian; Gleeson, Dermot; Thompson, Andrew; Muellhaupt, Beat; Stickel, Felix; Soyka, Michael; Goldman, David; Liang, Tiebing; Lumeng, Lawrence; Pirmohamed, Munir; Nalpas, Bertrand; Jacquet, Jean-Marc; Moirand, Romain; Nahon, Pierre; Naveau, Sylvie; Perney, Pascal; Botwin, Greg; Haber, Paul S.; Seitz, Helmut K.; Day, Christopher P.; Foroud, Tatiana M.; Daly, Ann K.; Cordell, Heather J.; Whitfield, John B.; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medical and Molecular Genetics, School of MedicineBackground and Aims Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and Results We analyzed 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. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and 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 patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10−17) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10−10) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10−8) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and 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 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. Conclusions Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.Item Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers(Wolters Kluwer, 2021) Whitfield, John B.; Masson, Steven; Liangpunsakul, Suthat; Mueller, Sebastian; Aithal, Guruprasad P.; Eyer, Florian; Gleeson, Dermot; Thompson, Andrew; Stickel, Felix; Soyka, Michael; Daly, Ann K.; Cordell, Heather J.; Foroud, Tatiana; Lumeng, Lawrence; Pirmohamed, Munir; Nalpas, Bertrand; Jacquet, Jean-Marc; Moirand, Romain; Nahon, Pierre; Naveau, Sylvie; Perney, Pascal; Haber, Paul S.; Seitz, Helmut K.; Day, Christopher P.; Mathurin, Philippe; Morgan, Timothy R.; Seth, Devanshi; GenomALC Consortium; Medicine, School of MedicineIntroduction: 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.Item Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia(Elsevier, 2016-04) Crabb, David W.; Bataller, Naga; Chalasani, Naga P.; Kamath, Patrick S.; Lucey, Michael; Mathurin, Philippe; McClain, Craig; McCullough, Arthur; Mitchell, Mack C.; Morgan, Timothy R.; Department of Medicine, IU School of MedicineHeavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines.