Ann Daly - Selected Publications#
Google scholar H-index 99 (38,707 citations, i10-index 277)
1. Nicoletti P, Devarbhavi H, Goel A, Venkatesan R, Eapen CE, Grove JI, Zafer S, Bjornsson E, Lucena MI, Andrade RJ, Pirmohamed M, Wadelius M, Larrey D, Maitland-van der Zee AH, Ibanez L, Watkins PB, Daly AK*, Aithal GP*. Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens. Clin Pharmacol Ther 2021;109:1125-1135. (*joint senior authors)
This recent study on drug-induced liver injury due to isoniazid treatment shows a clear association with genotype for the main isoniazid metabolizing enzyme based on genome-wide association analysis and points to the mechanism for liver toxicity with this drug involving drug metabolism rather than the adaptive immune response reported for other drugs causing idiosyncratic liver injury (see papers 5, 6, 7 and 9 below).
2. Schwantes-An TH, Darlay R, Mathurin P, Masson S, Liangpunsakul S, Mueller S, Aithal GP, Eyer F, Gleeson D, Thompson A, Muellhaupt B, Stickel F, Soyka M, Goldman D, Liang T, Lumeng L, Pirmohamed M, Nalpas B, Jacquet JM, Moirand R, Nahon P, Naveau S, Perney P, Botwin G, Haber PS, Seitz HK, Day CP, Foroud TM, Daly AK*, Cordell HJ*, Whitfield JB*, Morgan TR*, Seth D*. Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors. Hepatology 2021;73:1920-1931.(*joint senior authors)
As part of an international consortium (GenomALC funded by NIH), genome-wide association analysis of a large recently recruited cohort as well as meta analysis of cases in the UK Biobank indicated a very similar genetic susceptibility profile to that seen for nonalcoholic liver disease (see reference 4) with lipid metabolism rather than alcohol metabolism genes the important risk factors.
3. Govaere O, Cockell S, Tiniakos D, Queen R, Younes R, Vacca M, Alexander L, Ravaioli F, Palmer J, Petta S, Boursier J, Rosso C, Johnson K, Wonders K, Day CP, Ekstedt M, Orecic M, Darlay R, Cordell HJ, Marra F, Vidal-Puig A, Bedossa P, Schattenberg JM, Clement K, Allison M, Bugianesi E, Ratziu V, Daly AK*, Anstee QM* Transcriptomic profiling across the non-alcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis, Science Translational Medicine 2020, 12: eaba4448. (*joint senior authors)
This study has 106 citations to date and is the largest transcriptomics study on histologically characterised liver tissue from patients with nonalcoholic fatty liver disease and part of the EU Horizon 2020-funded EPoS study. Changes in expression of 25 genes appear crucial in progression from steatosis to advanced fibrosis and this gene signature was confirmed in a replication cohort. These genes represent potential disease biomarkers as well as novel drug targets.
4. Anstee QM, Darlay R, Cockell S, Meroni M, Govaere O, Tiniakos D, Burt AD, Bedossa P, Palmer J, Liu YL, Aithal GP, Allison M, Yki-Järvinen H, Vacca M, Dufour JF, Invernizzi P, Prati D, Ekstedt M, Kechagias S, Francque S, Petta S, Bugianesi E, Clement K, Ratziu V, Schattenberg JM, Valenti L, Day CP, Cordell HJ, Daly AK (2020). Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort. J Hepatol 2020 73:505-515. (200 citations)
Complementing paper 3 and also part of the EPoS study, this is also well cited (200 citations to date) and was the largest genome-wide association study on biopsy-proven cases of nonalcoholic liver disease. Four genes relevant to lipid metabolism were genome-wide significant. These data have subsequently contributed to establishment of a polygenic risk score for non-alcoholic fatty liver disease in a recent collaborative study (Vujkovic et al., Nature Genetics 2022; 54:761-771).
5. Koido M, Kawakami E, Fukumura J, Noguchi Y, Ohori M, Nio Y, Nicoletti P, Aithal GP, Daly AK, Watkins PB, Anayama H, Dragan Y, Shinozawa T, Takebe T. Polygenic architecture informs potential vulnerability to drug-induced liver injury. Nature Medicine 2020;26:1541-1548.
As an extension of paper 7, collaboration between the iDILIC network (Daly chief investigator) and a Japanese group resulted in development of a polygenic risk score for drug-induced liver injury based on both our genome-wide association data and studies in human hepatocytes. The novel score was significant for hepatotoxicity prediction with a novel drug under development.
6. Nicoletti P, Aithal GP, Chamberlain TC, Coulthard S, Alshabeeb M, Grove JI, Andrade RJ, Bjornsson E, Dillon JF, Hallberg P, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Wadelius M, Shen Y, Nelson MR, Daly AK (2019) Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles. Clin Pharmacol Ther 106:245-253.
This extends paper 9 and finds some additional HLA risk factors for drug-induced liver injury due to flucloxacillin but also confirms the strong association with HLA-B*57:01 in a considerably larger cohort.
7. Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernandez N, Ibanez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland- van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK (2017) Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-wide Association Study. Gastroenterology 152:1078-1089.
With 177 citations to date, this is the main report from the iDILIC study, an international study on the genetics of drug-induced liver injury. Daly is senior author and was also chief investigator on the study. The key finding is the first report of an association with HLA-A*33:01 which extends across drug-induced liver injury due to a number of different drug causes.
8. Liu Y-L, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JBS, Allison MED, Alexander GJ, Piguet A-C, Anty R, Donaldson P, Aithal GP, Francque S, Van Gaal L, Clement K, Ratziu V, Dufour J-F, Day CP, *Daly AK, *Anstee QM (2014) TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature Communications 5, 4309. (*joint senior authors)
Well cited paper (587 citations) which was the first to show that a variant in the gene TM6SF2 which is relevant to lipid metabolism was a risk factor for fibrosis progression in non-alcoholic liver disease. This important finding has subsequently been confirmed by a number of studies worldwide on both alcoholic and non-alcoholic liver disease (including papers 2 and 4).
9. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics 41:816-822.
Highly cited (1079 citations) paper from the UK-based DILIGEN study led by Daly which showed a very strong association between genotype for HLA-B*57:01 and susceptibility to flucloxacillin-induced liver injury. Individuals who carry at least one copy of this allele are 80 times more likely to develop this adverse drug reaction. Subsequently confirmed in larger cohort (paper 6).
10. Aithal GP, Day CP, Kesteven PJL, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717-719.
Landmark paper (1630 citations on Google Scholar) which was the first to show that genotype for two low activity-related variants in the CYP2C9 cytochrome P450 gene were significantly more common in patients who required a below average dose of warfarin due to slower metabolism. These patients were also more likely to suffer bleeding. This study informed a number of subsequent studies on individualising treatment with coumarin anticoagulants worldwide.
