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Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis.
Beaudoin, JJ, Liang, T, Tang, Q, Banini, BA, Shah, VH, Sanyal, AJ, Chalasani, NP, Gawrieh, S
Alcoholism, clinical and experimental research. 2021;(4):709-719
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Abstract
BACKGROUND Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH. METHODS A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity. RESULTS We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15-2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04-1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921). CONCLUSION PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.
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Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.
Vilar-Gomez, E, Pirola, CJ, Sookoian, S, Wilson, LA, Belt, P, Liang, T, Liu, W, Chalasani, N
The American journal of gastroenterology. 2021;(5):994-1006
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INTRODUCTION This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). METHODS PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. RESULTS The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. DISCUSSION This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.
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CA125-Guided Diuretic Treatment Versus Usual Care in Patients With Acute Heart Failure and Renal Dysfunction.
Núñez, J, Llàcer, P, García-Blas, S, Bonanad, C, Ventura, S, Núñez, JM, Sánchez, R, Fácila, L, de la Espriella, R, Vaquer, JM, et al
The American journal of medicine. 2020;(3):370-380.e4
Abstract
BACKGROUND The optimal diuretic treatment strategy for patients with acute heart failure and renal dysfunction remains unclear. Plasma carbohydrate antigen 125 (CA125) is a surrogate of fluid overload and a potentially valuable tool for guiding decongestion therapy. The aim of this study was to determine if a CA125-guided diuretic strategy is superior to usual care in terms of short-term renal function in patients with acute heart failure and renal dysfunction at presentation. METHODS This multicenter, open-label study randomized 160 patients with acute heart failure and renal dysfunction into 2 groups (1:1). Loop diuretics doses were established according to CA125 levels in the CA125-guided group (n = 79) and in clinical evaluation in the usual-care group (n = 81). Changes in estimated glomerular filtration rate (eGFR) at 72 and 24 hours were the co-primary endpoints, respectively. RESULTS The mean age was 78 ± 8 years, the median amino-terminal pro-brain natriuretic peptide was 7765 pg/mL, and the mean eGFR was 33.7 ± 11.3 mL/min/1.73m2. Over 72 hours, the CA125-guided group received higher furosemide equivalent dose compared to usual care (P = 0.011), which translated into higher urine volume (P = 0.042). Moreover, patients in the active arm with CA125 >35 U/mL received the highest furosemide equivalent dose (P <0.001) and had higher diuresis (P = 0.013). At 72 hours, eGFR (mL/min/1.73m2) significantly improved in the CA125-guided group (37.5 vs 34.8, P = 0.036), with no significant changes at 24 hours (35.8 vs 39.5, P = 0.391). CONCLUSION A CA125-guided diuretic strategy significantly improved eGFR and other renal function parameters at 72 hours in patients with acute heart failure and renal dysfunction.
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The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.
Berner, D, Hoja, U, Zenkel, M, Ross, JJ, Uebe, S, Paoli, D, Frezzotti, P, Rautenbach, RM, Ziskind, A, Williams, SE, et al
Human molecular genetics. 2019;(15):2531-2548
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LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.
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Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.
Vanninen, SUM, Leivo, K, Seppälä, EH, Aalto-Setälä, K, Pitkänen, O, Suursalmi, P, Annala, AP, Anttila, I, Alastalo, TP, Myllykangas, S, et al
PloS one. 2018;(9):e0203422
Abstract
During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.
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An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis.
Beaudoin, JJ, Long, N, Liangpunsakul, S, Puri, P, Kamath, PS, Shah, V, Sanyal, AJ, Crabb, DW, Chalasani, NP, Urban, TJ, et al
Scandinavian journal of gastroenterology. 2017;(11):1263-1269
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OBJECTIVES To elucidate the genetic variability between heavy drinkers with and without alcoholic hepatitis (AH). MATERIALS AND METHODS An exploratory genome-wide association study (GWAS; NCT02172898) was conducted comparing 90 AH cases with 93 heavy drinking matched controls without liver disease in order to identify variants or genes associated with risk for AH. Individuals were genotyped using the multi-ethnic genotyping array, after which the data underwent conventional quality control. Using bioinformatics tools, pathways associated with AH were explored on the basis of individual variants, and based on genes with a higher 'burden' of functional variation. RESULTS Although no single variant reached genome-wide significance, an association signal was observed for PNPLA3 rs738409 (p = .01, OR 1.9, 95% CI 1.1-3.1), a common single nucleotide polymorphism that has been associated with a variety of liver-related pathologies including alcoholic cirrhosis. Using the improved gene set enrichment analysis for GWAS tool, it was shown that, based on the single variants' trait-association p-values, multiple pathways were associated with risk for AH with high confidence (false discovery rate [FDR] < 0.05), including several pathways involved in lymphocyte activation and chemokine signaling, which coincides with findings from other research groups. Several Tox Functions and Canonical Pathways were highlighted using Ingenuity Pathway Analysis, with an especially conspicuous role for pathways related to ethanol degradation, which is not surprising considering the phenotype of the genotyped individuals. CONCLUSION This preliminary analysis suggests a role for PNPLA3 variation and several gene sets/pathways that may influence risk for AH among heavy drinkers.
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Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.
Dummer, R, Schadendorf, D, Ascierto, PA, Arance, A, Dutriaux, C, Di Giacomo, AM, Rutkowski, P, Del Vecchio, M, Gutzmer, R, Mandala, M, et al
The Lancet. Oncology. 2017;(4):435-445
Abstract
BACKGROUND There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. METHODS NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. FINDINGS Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25 (22%) patients in the dacarbazine group. INTERPRETATION Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy. FUNDING Array BioPharma and Novartis Pharmaceuticals Corporation.
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Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma.
Klein, O, Davis, ID, McArthur, GA, Chen, L, Haydon, A, Parente, P, Dimopoulos, N, Jackson, H, Xiao, K, Maraskovsky, E, et al
Cancer immunology, immunotherapy : CII. 2015;(4):507-18
Abstract
Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.
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Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron).
Ong, SY, Dolling, L, Dixon, JL, Nicoll, AJ, Gurrin, LC, Wolthuizen, M, Wood, EM, Anderson, GJ, Ramm, GA, Allen, KJ, et al
BMJ open. 2015;(8):e008938
Abstract
INTRODUCTION HFE p.C282Y homozygosity is the most common cause of hereditary haemochromatosis. There is currently insufficient evidence to assess whether non-specific symptoms or hepatic injury in homozygotes with moderately elevated iron defined as a serum ferritin (SF) of 300-1000 µg/L are related to iron overload. As such the evidence for intervention in this group is lacking. We present here methods for a study that aims to evaluate whether non-specific symptoms and hepatic fibrosis markers improve with short-term normalisation of SF in p.C282Y homozygotes with moderate elevation of SF. METHODS AND ANALYSIS Mi-iron is a prospective, multicentre, randomised patient-blinded trial conducted in three centres in Victoria and Queensland, Australia. Participants who are HFE p.C282Y homozygotes with SF levels between 300 and 1000 μg/L are recruited and randomised to either the treatment group or to the sham treatment group. Those in the treatment group have normalisation of SF by 3-weekly erythrocytapheresis while those in the sham treatment group have 3-weekly plasmapheresis and thus do not have normalisation of SF. Patients are blinded to all procedures. All outcome measures are administered prior to and following the course of treatment/sham treatment. Patient reported outcome measures are the Modified Fatigue Impact Scale (MFIS-primary outcome), Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study 36-item short form V.2 (SF36v2) and Arthritis Impact Measurement Scale 2 short form (AIMS2-SF). Liver injury and hepatic fibrosis are assessed with transient elastography (TE), Fibrometer and Hepascore, while oxidative stress is assessed by measurement of urine and serum F2-isoprostanes. ETHICS AND DISSEMINATION This study has been approved by the Human Research Ethics Committees of Austin Health, Royal Melbourne Hospital and Royal Brisbane and Women's Hospital. Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION Trial identifier: NCT01631708; Registry: ClinicalTrials.gov.
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FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study.
Kaczirek, K, Ciuleanu, TE, Vrbanec, D, Marton, E, Messinger, D, Liegl-Atzwanger, B, Wrba, F, Knittelfelder, R, Lindner, E, Zielinski, CC, et al
Clinical colorectal cancer. 2015;(2):91-8
Abstract
BACKGROUND This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab. PATIENTS AND METHODS Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups. RESULTS Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups. CONCLUSION These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.