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Browsing by Author "Nicoletti, Paola"
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Item Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study(Elsevier, 2017-04) Nicoletti, Paola; Aithal, Guruprasad P.; Bjornsson, Einar S.; Andrade, Raul J.; Sawle, Ashley; Arrese, Marco; Barnhart, Huiman X.; Bondon-Guitton, Emmanuelle; Hayashi, Paul H.; Bessone, Fernando; Carvajal, Alfonso; Cascorbi, Ingolf; Cirulli, Elizabeth T.; Chalasani, Naga; Conforti, Anita; Coulthard, Sally A.; Daly, Mark J.; Day, Christopher P.; Dillon, John F.; Fontana, Robert J.; Grove, Jane I.; Hallberg, Pär; Hernández, Nelia; Ibáñez, Luisa; Kullak-Ublick, Gerd A.; Laitinen, Tarja; Larrey, Dominique; Lucena, M. Isabel; Maitland-van der Zee, Anke H.; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Powell, Elizabeth E.; Qin, Shengying; Serrano, Jose; Stephens, Camilla; Stolz, Andrew; Wadelius, Mia; Watkins, Paul B.; Floratos, Aris; Shen, Yufeng; Nelson, Matthew R.; Urban, Thomas J.; Daly, Ann K.; International Drug-Induced Liver Injury Consortium; Drug-Induced Liver Injury Network Investigators; International Serious Adverse Events Consortium; Medicine, School of MedicineBACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.Item Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury(Elsevier, 2023) Chalasani, Naga; Li, Yi-Ju; Dellinger, Andrew; Navarro, Victor; Bonkovsky, Herbert; Fontana, Robert J.; Gu, Jiezhun; Barnhart, Huiman; Phillips, Elizabeth; Lammert, Craig; Schwantes-An, Tae-Hwi; Nicoletti, Paola; Kleiner, David E.; Hoofnagle, Jay H.; Drug Induced Liver Injury Network; Medicine, School of MedicineBackground & aims: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). Methods: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661). Results: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003). Conclusion: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. Impact and implications: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.Item Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim-Sulfamethoxazole Induced Liver Injury(Wolters Kluwer, 2021) Li, Yi-Ju; Phillips, Elizabeth J.; Dellinger, Andrew; Nicoletti, Paola; Schutte, Ryan; Li, Danmeng; Ostrov, David A.; Fontana, Robert J.; Watkins, Paul B.; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Barnhart, Huiman; Chalasani, Naga; Drug-induced Liver Injury Network (DILIN); Medicine, School of MedicineBackground and aims: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI. Approach and results: European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 × 10-5 ). For the African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at position 67 in HLA-B*35:01 to be the predictive binding sites for SMX metabolites. Conclusions: HLA-B*14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B*35:01 may be a potential genetic risk factor for African Americans.Item Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate(Elsevier, 2023) Nicoletti, Paola; Dellinger, Andrew; Li, Yi Ju; Barnhart, Huiman X.; Chalasani, Naga; Fontana, Robert J.; Odin, Joseph A.; Serrano, Jose; Stolz, Andrew; Etheridge, Amy S.; Innocenti, Federico; Govaere, Olivier; Grove, Jane I.; Stephens, Camilla; Aithal, Guruprasad P.; Andrade, Raul J.; Bjornsson, Einar S.; Daly, Ann K.; Lucena, M. Isabel; Watkins, Paul B.; Drug-Induced Liver Injury Network (DILIN); International Drug-Induced Liver Injury Consortium (iDILIC); Prospective European Drug-Induced Liver Injury (Pro-Euro DILI) Investigators; Medicine, School of MedicineBackground & aims: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). Methods: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. Results: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. Conclusions: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.Item Minocycline Hepatotoxicity: Clinical characterization and identification of HLA-B* 35:02 as a risk factor(Elsevier, 2017) Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga; Serrano, Jose; Stolz, Andrew; Daly, Ann; Aithal, Guruprasad; Dillon, John; Navarro, Victor; Odin, Joseph; Barnhart, Huiman; Ostrov, David; Long, Nanye; Cirulli, Elizabeth Theresa; Watkins, Paul Brent; Fontana, Robert John; Department of Medicine, IU School of MedicineBackground & Aims Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Methods Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Results Among the 25 cases, 80% were female, median age was 19 years and median latency from drug start to DILI onset was 318 days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077 U/L (range: 63 to 2,333), median bilirubin 4.5 mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8–89.8, p = 2.5 × 10−8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. Conclusion HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Lay summary Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.Item A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury(Elsevier, 2019) Cirulli, Elizabeth T.; Nicoletti, Paola; Abramson, Karen; Andrade, Raul J.; Bjornsson, Einar S.; Chalasani, Naga; Fontana, Robert J.; Hallberg, Pär; Li, Yi Ju; Lucena, M. Isabel; Long, Nanye; Molokhia, Mariam; Nelson, Matthew R.; Odin, Joseph A.; Pirmohamed, Munir; Rafnar, Thorunn; Serrano, Jose; Stefansson, Kari; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Watkins, Paul B.; Medicine, School of MedicineBackground & Aims We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, non-receptor type 22 gene (PTPN22) (odds ratio [OR], 1.44; 95% CI, 1.28–1.62; P=1.2x10–9 and replicated the finding in the validation set (OR, 1.48; 95% CI, 1.09–1.99; P=.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR, 1.62; 95% CI, 1.32–1.98; P=4.0x10–6; allele frequency=13.3%), but the polymorphism was associated with DILI of other causes (OR, 1.37; 95% CI, 1.21–1.56; P= 1.5x10–6; allele frequency=11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.