Browsing by Author "Liang, Tiebing"
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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 Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking(Wiley Blackwell (Blackwell Publishing), 2015-07) Kosobud, Ann E. K.; Wetherill, Leah; Plawecki, Martin H.; Kareken, David A.; Liang, Tiebing; Nurnberger, John L.; Windisch, Kyle; Xuei, Xiaoling; Edenberg, Howard J.; Foroud, Tatiana M.; O’Connor, Sean J.; Department of Psychiatry, IU School of MedicineBACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.Item ADH and ALDH polymorphisms and alcohol dependence in Mexican and Native Americans(Taylor & Francis, 2012) Ehlers, Cindy L.; Liang, Tiebing; Gizer, Ian R.; Medicine, School of MedicineBackground: Ethanol is primarily metabolized in the liver by two rate-limiting reactions: conversion of ethanol to acetaldehyde by alcohol dehydrogenase (ADH) and subsequent conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). ADH and ALDH exist in multiple isozymes that differ in their kinetic properties. Notably, polymorphisms within the genes that encode for these isozymes vary in their allele frequencies between ethnic groups, and thus, they have been considered as candidate genes that may differentially influence risk for the development of alcohol dependence across ethnic groups. Objectives and methods: Associations between alcohol dependence and polymorphisms in ADH1B, ADH1C, and ALDH2 were compared in a community sample of Native Americans (n 791) living on reservations and Mexican Americans (n 391) living within the same county. Results: Two Mexican Americans and no Native Americans possessed one ALDH2*2 allele. Presence of at least one ADH1B*2 allele was found in 7% of the Native Americans and 13% of the Mexican Americans, but was only associated with protection against alcohol dependence in the Mexican Americans. Presence of at least one ADH1B*3 allele was found in 4% of the Native Americans and 2% of the Mexican Americans, but was associated with protection against alcohol dependence only in the Native Americans. No associations between alcohol dependence and polymorphisms in ADH1C were found. Conclusions and scientific significance: Polymorphisms in ADH1B are protective against alcoholism in these two populations; however, these findings do not explain the high prevalence of alcoholism in these populations.Item ADH1B*2 is Associated With Reduced Severity of Nonalcoholic Fatty Liver Disease in Adults, Independent of Alcohol Consumption(Elsevier, 2020) Vilar-Gomez, Eduardo; Sookoian, Silvia; Pirola, Carlos Jose; Liang, Tiebing; Gawrieh, Samer; Cummings, Oscar; Liu, Wanqing; Chalasani, Naga; Medicine, School of MedicineBackground & Aims Alcohol dehydrogenase 1B (ADH1B) is involved in alcohol metabolism. The allele A ( ADH1B*2) of rs1229984: A>G variant in ADH1B is associated a higher alcohol metabolizing activity, compared to the ancestral allele G ( ADH1B*1). Moderate alcohol consumption is associated with reduced severity of nonalcoholic fatty liver disease (NAFLD), based on histologic analysis, compared with no alcohol consumption. However, it is unclear whether ADH1B*2 modifies the relationship between moderate alcohol consumption and severity of NAFLD. We examined the association between ADH1B*2 and moderate alcohol consumption and histologic severity of NAFLD. Methods We collected data from 1557 multi-ethnic adult patients with biopsy-proven NAFLD enrolled into 4 different studies conducted by the NASH Clinical Research Network. Histories of alcohol consumption were obtained from answers to standardized questionnaires. Liver biopsies were analyzed by histology and scored centrally according to the NASH CRN criteria. We performed covariate adjusted logistic regressions to identify associations between histologic features of NAFLD severity and moderate alcohol consumption and/or ADH1B*2. Results A higher proportion of Asians/Pacific Islanders/Hawaiians carried the ADH1B*2 allele (86%) than other racial groups (4%–13%). However, the study population comprised mostly non-Hispanic whites (1153 patients, 74%), so the primary analysis focused on this group. Among them, 433 were moderate drinkers and 90 were ADH1B*2 carriers. After we adjusted for confounders, including alcohol consumption status, ADH1B*2 was associated with lower frequency of steatohepatitis (odds ratio [OR], 0.52; P<.01) or fibrosis (odds ratio, 0.69; P=.050) compared with ADH1B*1. Moderate alcohol consumption (g/day) reduced the severity of NAFLD in patients with ADH1B*1 or ADH1B*2. However, ADH1B*2, compared to ADH1B*1, was associated with a reduced risk of definite NASH ( ADH1B*2 OR, 0.80; P<.01 vs ADH1B*1 OR, 0.96; P=.036) and a reduced risk of an NAFLD activity score of 4 or higher ( ADH1B*2 OR, 0.83; P=.012 vs ADH1B*1 OR, 0.96; P=.048) ( P<.01 for the difference in the effect of moderate alcohol consumption between alleles). The relationship between body mass index and NAFLD severity was significantly modified by ADH1B*2, even after we controlled for alcohol consumption. Conclusions ADH1B*2 reduces the risk of NASH and fibrosis in adults with NAFLD regardless of alcohol consumption status. ADH1B*2 might modify the association between high body mass index and NAFLD severity.Item Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats(Wiley Blackwell (Blackwell Publishing), 2014-05) Yong, Weidong; Spence, John Paul; Eskay, Robert; Fitz, Stephanie D.; Damadzic, Ruslan; Lai, Dongbing; Foroud, Tatiana; Carr, Lucinda G.; Shekhar, Anantha; Chester, Julia A.; Heilig, Markus; Liang, Tiebing; Department of Medicine, IU School of MedicineBACKGROUND: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. METHODS: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. RESULTS: Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. CONCLUSIONS: This study identified Crhr2 as a candidate gene of interest underlying the chromosome 4 QTL for alcohol consumption that was previously identified in the P and NP model. Crhr2 promoter polymorphism is associated with reduced mRNA expression in certain brain regions, particularly the amygdala, and lowered the density of CRF2 receptor in the amygdala of iP compared to iNP rats. Together, these differences between the animals may contribute to the drinking disparity as well as the anxiety differences of the P and NP rats.Item Apolipoprotein B and PNPLA3 Double Heterozygosity in a Father–Son Pair With Advanced Nonalcoholic Fatty Liver Disease(Wiley, 2019) Jansson-Knodell, Claire L.; Gawrieh, Samer; McIntyre, Adam D.; Liang, Tiebing; Hegele, Robert A.; Chalasani, Naga; Medicine, School of MedicineItem Association of the ALDH1A1*2 promoter polymorphism with alcohol phenotypes in young adults with or without ALDH2*2(Wiley, 2013) Otto, Jacqueline M.; Hendershot, Christian S.; Collins, Susan E.; Liang, Tiebing; Wall, Tamara L.; Medicine, School of MedicineBackground: Prior studies suggest a possible association of a promoter polymorphism in the ALDH1A1 gene ( ALDH1A1*2 ) with alcohol use or dependence. The aim of this study was to examine the association of ALDH1A1*2 with drinking behaviors in Asian young adults and to examine ALDH2 genotype as a potential moderator of these associations. Methods: Asian young adults (n = 951) were recruited from 2 college sites for studies of genetic associations with alcohol use behavior. Participants completed comprehensive background questionnaires on demographics and drinking behavior. Fingertip blood samples were obtained for DNA extraction and analysis. Results: Participants with the ALDH2*1/*2 genotype reported significantly lower levels (frequency and quantity) of drinking within the last 90 days, fewer numbers of heavy drinking episodes within the last 90 days, and lower lifetime maximum consumption levels compared with ALDH2*1/*1 participants. There were no significant main effects of ALDH1A1*2 on any drinking variables, nor was there a significant interaction between ALDH2 and ALDH1A1 genotypes on drinking outcomes. Conclusions: The association of ALDH2*2 with reduced alcohol consumption replicates previous findings across numerous studies. Although ALDH1A1*2 was not associated with drinking levels, the lack of an ALDH1A1*2 effect in ALDH2*2 individuals is consistent with the only other study that has examined these associations in East Asian populations.Item BDNF and stress/mood-related interactions on emotional disorder symptoms, executive functioning, and deliberate self-harm(Elsevier, 2023) Guillot, Casey R.; Kelly, Megan E.; Phillips, Noah B.; Su, Mei-Yi; Douglas, Megan E.; Poe, Darian J.; Berman, Mitchell E.; Liang, Tiebing; Medicine, School of MedicineSome prior research has suggested that the brain-derived neurotrophic factor (BDNF) gene may amplify responses related to life stress (e.g., depression and anxiety) or associated with negative moods (e.g., self-harm and diminished cognitive functioning). The purpose of this study was to investigate whether stress/mood-related associations with depressive and anxiety symptoms, deliberate self-harm, and executive functioning (EF) are moderated by genotypic variations in BDNF rs10835210 (a relatively understudied BDNF polymorphism) in a nonclinical sample. As part of a larger study, European American social drinkers (N = 132; 43.9% female; M age = 26.0, SD = 7.6) were genotyped for BDNF rs10835210 and were administered self-report measures of subjective life stress, depressive and anxiety symptoms, and history of non-suicidal self-injury (NSSI) and behavioral measures of EF and deliberate self-harm. Results indicated that BDNF significantly moderated the life stress associations with depressive symptoms and NSSI, the anxious mood association with EF, and the depressed mood association with deliberate self-harm behavior. Each of these BDNF × stress/mood interactions were characterized by stress/mood associations that were stronger in individuals with the AA genotype (homozygous for the minor allele) than in individuals possessing a genotype that included the major allele (AC or CC). The main limitations of the present study were use of a cross-sectional design, modest sample size, and investigating only one BDNF polymorphism. Despite these limitations and though preliminary, current findings suggest that variations in BDNF may confer vulnerability to stress or mood, which may result in more adverse emotional, cognitive, or behavioral outcomes.Item Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats(BMC, 2010-02-03) Liang, Tiebing; Kimpel, Mark W.; McClintick, Jeanette N.; Skillman, Ashley R.; McCall, Kevin; Edenberg, Howard J.; Carr, Lucinda G.; Medicine, School of MedicineSelectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ greatly in alcohol preference, in part due to a highly significant quantitative trait locus (QTL) on chromosome 4. Alcohol consumption scores of reciprocal chromosome 4 congenic strains NP.P and P.NP correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in five brain regions of alcohol-naïve inbred alcohol-preferring and P.NP congenic rats: amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex. Results Within the QTL region, 104 cis-regulated probe sets were differentially expressed in more than one region, and an additional 53 were differentially expressed in a single region. Fewer trans-regulated probe sets were detected, and most differed in only one region. Analysis of the average expression values across the 5 brain regions yielded 141 differentially expressed cis-regulated probe sets and 206 trans-regulated probe sets. Comparing the present results from inbred alcohol-preferring vs. congenic P.NP rats to earlier results from the reciprocal congenic NP.P vs. inbred alcohol-nonpreferring rats demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in at least one brain region. Conclusions Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by consistent results in two independent experiments with reciprocal congenic rats. These genes are strong candidates for affecting alcohol preference in the inbred alcohol-preferring and inbred alcohol-nonpreferring rats.