The Pharmacogenomics and Personalized Medicine laboratory focuses on understanding how genetic information can be used to predict, diagnosis and treat disease. We are particularly focused on identifying genetic variation that predicts response to medications and understanding molecular mechanisms of drug toxicity.
Response to prescription medications is extremely variable. For many major classes of drugs, only ~50% of patients experience the desired therapeutic response. In addition, some patients suffer from adverse reactions to medications that can be severe or even life-threatening. Why some people respond to a drug and some people are harmed by them is to a large extent influenced by genetic variability. We are attempting to identify genetic variants that influence response to medication, particularly chemotherapeutic drugs, in various global populations.
Inherited disorders of cholesterol metabolism are some of the most common genetic diseases, and pose a significant risk for heart attack and stroke. Yet the diagnosis of these disorders is still largely based on clinical and biochemical features, rather than a detailed understanding of the molecular defect responsible for an individual’s disease. We are exploring the use of new DNA genotyping and sequencing technologies to develop rapid and accurate genetic tests for this group of disorders.
Human genetic studies have identified numerous genetic variants that are associated with disease risk or response to medication, but understanding the functional impact of these variants and the mechanisms by which they influence the traits with which they are associated remains a major hurdle. We are using recently described genome-editing tools to establish isogenic cell lines as cellular models in which to probe the functional importance of drug-response alleles.
Liam Brunham is an assistant professor in the Department of Medicine at the Yong Loo Lin School of Medicine, National University of Singapore, and an assistant principal investigator in the Translational Laboratory for Genetic Medicine, A*STAR.
Folefac Aminkeng is an Assistant Principal Investigator and the Associate Head of the Pharmacogenomics and Personalized Medicine Program at the Translational Laboratory in Genetic Medicine at the Agency for Science, Technology and Research (A*STAR). He is also an Adjunct Assistant Professor in the Department of Pharmacology at the Yong Loo Lin School of Medicine, National University of Singapore. His major research focus is on understanding the genetic and mechanistic basis of adverse drug reactions and developing pharmacogenomics tools for Precision Medicine.
Sahar graduated from the Shahid Beheshti University of Medical Sciences, Tehran, Iran with a Pharm.D degree (doctor of pharmacy) in 2015 and worked on evaluating the effect of natural extractions on animal models of hepatocellular carcinoma as her thesis project. She then joined the Pharmacogenomics and Personalized Medicine group as a research assistant by international SIPGA scholarship. She is currently working on Pharmacogenomics of adverse drug reactions especially anticancer drugs.
Dionne F, Aminkeng F, Bhavsar AP, Groeneweg G, Smith A, Visscher H, Rassekh SR, Ross C, Carleton B. An initial health economic evaluation of pharmacogenomic testing in patients treated for childhood cancer with anthracyclines. Pediatr Blood Cancer. 2018 Mar;65(3). doi: 10.1002/pbc.26887.
Kay C, Collins JA, Wright GEB, Baine F, Miedzybrodzka Z, Aminkeng F, Semaka AJ, McDonald C, Davidson M, Madore SJ, Gordon ES, Gerry NP, Cornejo-Olivas M, Squitieri F, Tishkoff S, Greenberg JL, Krause A, Hayden MR. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am J Med Genet B Neuropsychiatr Genet. 2018 Feb 20. doi: 10.1002/ajmg.b.32618.
Drögemöller, B. Monzon, J. Bhavsar, A. Borrie, A. Brooks, B. Wright, G. Liu, G. Fadhel, E. Renouf, D. Kollmannsberger, C. Bedard, P. Aminkeng, F. Hildebrand, C.,Gunaretnam, E. Critchley, C. Chen, Z. Brunham, L. Hayden, M. Ross, C. Gelmon, K., Carleton, B. Genetic variation in SLC16A5 confers protection from cisplatin-induced ototoxicity in adult testicular cancer patients. Jama Oncology. 2017 Apr 27. doi: 10.1001/jamaoncol.2017.0502.
Ang HX, Chan SL, Sani LL, Quah CB, Brunham LR, Tan BOP, Winther MD. Development and validation of algorithms for the detection of statin myopathy signals from electronic medical records. Clin Pharmacol Ther. 2017 May;101(5):667-674. doi: 10.1002/cpt.526. Epub 2017 Jan 21.
Cirstea M, Walley KR, Russell JA, Brunham LR, Genga KR, Boyd JH. Pharmacogenomics in Asia: a systematic review on current trends and novel discoveries.
Pharmacogenomics. 2017 Jun;18(9):891-910. doi: 10.2217/pgs-2017-0009. Epub 2017 Jun 8.
Woei-Yuh Saw, Erwin Tantoso, Husna Begum, Lihan Zhou, Ruiyang Zou, Cheng He, Sze Ling Chan, Linda Wei-Lin Tan, Lai Ping Wong, Wenting Xu, Don Kyin Nwe Moong, Yenly Lim, Bowen Li, E Nisha Pillai, Trevor Peterson, Tomasz Bielawny, Peter Meikle, Piyushukumar Mundra, Wei-Yen Lim, Ma Luo, Kee-Seng Chia, Rick Twee-Hee Ong, Liam Brunham, Chiea Chuen Khor, Heng Phon Too, Richie Soong, Markus Wenk, Peter Little, and Yik-Ying Teo. Establishing multiple omics baseline for three Southeast Asian ethnic groups in the Singapore Integrative Omics Cohort. Nature Communications. In Press.
Chan SL, Chua APG, Aminkeng F, Chee CBE, Jin S, Loh M, Gan SH, Wang YT, Brunham LR. Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients. PLoS One. 2017 Oct 16;12 (10):e0186200. doi: 10.1371/journal.pone.0186200. eCollection 2017.
Aminkeng F, Ross CJD, Rassekh SR, Rieder MJ, Bhavsar AP, Sanatani S, Bernstein D, Hayden MR, Amstutz U, Carleton BC. Pharmacogenomic Screening for Anthracycline-induced Cardiotoxicity in Childhood Cancer. Br J Clin Pharmacol. 2017 May; 83(5):1143-1145.
Maillet A, Tan K, Chai X, Sadananda SN, Mehta A, Ooi J, Hayden MR, Pouladi MA, Ghosh S, Shim W, Brunham LR. Modeling doxorubicin-induced cardiotoxicity in human pluripotent stem cell derived-cardiomyocytes. Scientific Reports. 2016.
Chan SL, Samaranayake N, Ross CJ, Toh MT, Carleton B, Hayden MR, Teo YY, Dissanayake VH, Brunham LR. Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics. Pharmacogenet Genomics. 2016 Jan;26(1):28-39. doi: 10.1097/FPC.0000000000000182.
Brunham LR. HDL as a Causal Factor in Atherosclerosis: Insights from Human Genetics. Curr Atheroscler Rep. 2016 Dec;18(12):71.
Chan SL, Tham M2, Tan SH, Loke C, Foo B, Fan Y, Ang PS, Brunham LR, Sung C. Development and validation of algorithms for the detection of statin myopathy signals from electronic medical records. Clin Pharmacol Ther. 2016 Oct 5. doi: 10.1002/cpt.526.
Chan SL, Ang X, Sani LL, Ng HY, Winther M2, Liu JJ, Brunham LR, Chan A. Prevalence and characteristics of adverse drug reactions at admission to hospital: a prospective observational study. Br J Clin Pharmacol. 2016 Sep 19. doi: 10.1111/bcp.13081.
Aminkeng F, Ross CJD, Rassekh SR, Hwang S, Rieder MJ, Bhavsar AP, Smith A, Sanatani S, Gelmon KA, Bernstein D, Hayden MR, Amstutz U, Carleton BC, CPNDS Clinical Practice Recommendations Group. Recommendations for Genetic Testing to Reduce the Incidence of Anthracycline-induced Cardiotoxicity. Br J Clin Pharmacol. 2016 Sep; 82(3):683-95.
Chan SL, Jin S, Loh M, Brunham LR. Progress in understanding the genomic basis for adverse drug reactions: a comprehensive review and focus on the role of ethnicity. Pharmacogenomics. 2015 Jul;16(10):1161-78.
Aminkeng F, Bhavsar AP, Visscher H, Rassekh SR, Li Y, Lee JW, Brunham LR, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Amstutz U, Rieder MJ, Bernstein D, Carleton BC, Hayden MR, Ross CJ; Canadian Pharmacogenomics Network for Drug Safety Consortium. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015 Sep; 47(9):1079-84.
Brunham LR, Chan SL, Li R, Aminkeng F, Liu X, Saw WY, Ong RT, Pillai EN, Carleton BC, Toh D, Tan SH, Koo SH, Lee EJ, Chia KS, Ross CJ, Hayden MR, Sung C, Teo YY. Pharmacogenomic diversity in Singaporean populations and Europeans. Pharmacogenomics J. 2014 May 27. doi: 10.1038/tpj.2014.22. PMID: 24861855
Lee JW, Aminkeng F, Bhavsar AP, Shaw K, Carleton BC, Hayden MR, Ross CJ. The Emerging Era of Pharmacogenomics: Current Successes, Future Potential, and Challenges. Clin Genet. 2014 Jul; 86(1):21-8. (Lee JW and Aminkeng F contributed equally to this publication).
Aminkeng F, Ross CJD, Rassekh SR, Brunham LR, Sistonen J, Dube MP, Ibrahim M, Nyambo TB, Omar SA, Froment A, Bodo JM, Tishkoff SA, Carleton BC, Hayden MR, and The Canadian Pharmacogenomics Network for Drug Safety Consortium. Higher Frequency of Genetic Variants Conferring Increased Risk for ADRs for Commonly Used Drugs Treating Cancer, AIDS and Tuberculosis in Persons of African Descent. Pharmacogenomics J. 2014 Apr; 14(2):160-70.
Brunham LR, Hayden MR. Hunting human disease genes: lessons from the past, challenges for the future. Human genetics. Mar 17 2013.
Brunham LR, Hayden MR. Medicine. Whole-genome sequencing: the new standard of care? Science. Jun 1 2012;336(6085):1112-1113.
Brunham LR, Lansberg PJ, Zhang L, Miao F, Carter C, Hovingh GK, Visscher H, Jukema JW, Stalenhoef AF, Ross CJ, Carleton BC, Kastelein JJ, Hayden MR. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.Pharmacogenomics J. Jun 2012;12(3):233-237.
Kruit JK, Wijesekara N, Westwell-Roper C, Vanmierlo T, de Haan W, Bhattacharjee A, Tang R, Wellington CL, LütJohann D, Johnson JD, Brunham LR, Verchere CB, Hayden MR. Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired beta-cell function. Diabetes. Mar 2012;61(3):659-664.
Brunham LR, Tietjen I, Bochem AE, Singaraja RR, Franchini PL, Radomski C, Mattice M, Legendre A, Hovingh GK, Kastelein JJ, Hayden MR.Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans. Clinical genetics. Jun 2011;79(6):575-581.
Vergeer M, Brunham LR, Koetsveld J, Kruit JK, Verchere CB, Kastelein JJ, Hayden MR, Stroes ES. Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction. Diabetes Care. Apr 2010;33(4):869-874.
Brunham LR, Singaraja RR, Duong M, Timmins JM, Fievet C, Bissada N, Kang MH, Samra A, Fruchart JC, McManus B, Staels B, Parks JS, Hayden MR. Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis.Arterioscler Thromb Vasc Biol. Apr 2009;29(4):548-554
Brunham LR, Kastelein JJ, Hayden MR. ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease.JAMA. Nov 5 2008;300(17):1997-1998; author reply 1998.
Brunham LR, Kruit JK, Verchere CB, Hayden MR. Cholesterol in islet dysfunction and type 2 diabetes. J Clin Invest. Feb 2008;118(2):403-408.
Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, Verchere CB, Hayden MR. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment.Nat Med. Mar 2007;13(3):340-347.
Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JM, Pape TD, Coburn BA, Bissada N, Staels B, Groen AK, Hussain MM, Parks JS, Kuipers F, Hayden MR. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. Apr 2006;116(4):1052-1062.
Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levelsCirc Res. Sep 29 2006;99(7):672-674.
Brunham LR, Singaraja RR, Hayden MR. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.Annu Rev Nutr. 2006;26:105-129.
Brunham LR, Singaraja RR, Pape TD, Kejariwal A, Thomas PD, Hayden MR. Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene PLoS Genet. Dec 2005;1(6):e83.
Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol. Aug 1 2003;23(8):1322-1332.
Dr Singh Nongmaithem Sadananda has won a competitive Travel Grant awarded by the Asia Pacific Federation of International Atherosclerosis Society to attend the ISA 2015 held at Amsterdam, 24-26 May 2015.
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