Background and Scientific Accomplishments of the PGRN Through 2011

Note: This is an archived page that is not updated.

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2011 Poor response to glucocorticoids in asthmatics is linked to variants in the GLCCI1 gene. (Weiss group: September 29, 2011 NEJM 365(13):1173-83)

2011 Family of four receives whole genome analysis of their health risks. (Altman group: September 15, 2011 PLoS Genetics 7(9): e1002280)

2011 When taken together, the lipid-lowering agent pravastatin and the antidepressant paroxetine increase blood sugar levels. (Altman group: May 25, 2011 Clinical Pharmacology & Therapeutics 90(1):133-42)

2010     A person's genome sequence is used to analyze his risk of diseases and adverse drug responses. (Altman group:  May 1, 2010 Lancet 375(9725):1525-1535) NIGMS news release

2009     A CYP2C19 gene variant carried by about a third of the population is found to play a major role in this group’s response to an anti-clotting medicine, clopidogrel (Plavix). (Shuldiner group: August 26, 2009 JAMA 302(8):849-857) NIGMS media availability

2009     PharmGKB has 3,246 registered users; 345 dataset submissions; 13,830 unique variants; 8,282 subjects with both genotype and phenotype data; 461,324 phenotypes measured; 3,390 literature annotations; 3,251,316 total variants observed; 9,570 genotype/phenotype pairs

2009     A new method is developed to help doctors determine a patient’s optimal dose of the blood thinner, warfarin. The method was devised using data from thousands of genetically and geographically diverse patients. (Altman, Johnson, McLeod and Roden groups: Feb 19, 2009 NEJM 360:753-764) NIGMS news release

2008     Leaders at the National Institutes of Health and the Center for Genomic Medicine in Japan form the Global Alliance for Pharmacogenomics. The consortium aims to identify genetic factors that contribute to individual responses to medicines, including rare and dangerous side effects. (April 2008) NIGMS news release

2007     FDA approves updated labeling for the blood-thinning agent, warfarin, to state that people's genetic makeup may influence how they respond to the drug. (August 2007) FDA news release Link to external Web site

2007     Inherited variations in certain genes are linked to toxic side effects of chemotherapy in children undergoing ALL treatment. (Relling group: May 15, 2007 Blood 109:4151-4157) St. Jude Children’s Research Hospital news release Link to external Web site

2006     FDA advisory committee plans to hold an advisory meeting to consider changing tamoxifen labeling to recommend that all women prescribed tamoxifen be tested for CYP2D6 genotype (October 2006).

2006     A variant of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) gene in African Americans (who have the allele at 30% frequency compared to 2% in European Americans) may account for variable response to the statins that are used to treat cardiovascular disease. Two hapolotypes of HMGCR in African Americans reduce response to statins. (Krauss group: Circulation 112 (17) Supplement II:725 (Abstract))

2006     PharmGKB has 1,940 registered users; 95 phenotype submissions; 64 genes with data; 5540 unique variants; 12,710 subjects with genotypes; 5,305 subjects with both genotype and phenotype data; 141,759 phenotypes measured; 1,391 literature annotations; 1,316,994 total variants observed

2006     CYP2A6 genotype predicts likelihood of smoking cessation in response to nicotine patches (Benowitz group: Apr 2006 Mol Psychiatry 11:400-409; Jun 2006 Clin Pharmacol Ther 79:600-608)

2005     PharmGKB has 1900 registered users; 264 PK/PD genes with data; 5540 unique variants; 113 phenotype submissions; 40,000 Web site visitors/month

2005     Examined 137 patients with torsades de point and 700 controls to find 2 genome-wide risk alleles for long QT syndrome (Roden group: Oct 2005 Circulation Abstract)

2005     Polymorphisms in beta2-adrenergic receptor are associated with survival among patients who receive beta-blocker therapy after a heart attack (McLeod group: Sep 28. 2005 JAMA 294:1526-1533)

2005   A new method avoids multiple comparison problems in whole genome analysis. (Weiss group: Jul 2005 Nature Genetics 37:683-691).

2005     Variants in the gene for vitamin K epoxide reductase complex 1 (VKORC1) affect response to the anticoagulant warfarin (McLeod group: Jun 2, 2005 NEJM 352:2285-2293)

2005     Polymorphisms of beta-1 receptor associated with reduced effect on ejection fraction of beta adrenergic blocking agents (Johnson group: Mar 2005 Clin Pharmacol Ther 77:127-137, Apr 2005 Pharmacogenet Genomics 15:227-234)

2005     The FDA issues guidelines encouraging pharmaceutical companies to gather and submit information on how genetic variations affect drug response (March 2005)

2005     Nicotine elimination rate is found to be highly heritable (Benowitz group: Feb 2005 Pharmacogenet Genomics 15:115-125)

2004-2006 Functional annotation of about 90 SNPs in 12 membrane transporters in the SLC and ABC superfamilies (Giacomini group: Feb 2006 Genome Res 16:223-230)

2004-2006  Predictors of ALL relapse identified using candidate genes and genome-wide approaches (Relling group: 2004 NEJM 351:533-542; 2005 Cancer Cell 7:375-386; 2005 Blood 105:4752-4758, 2006 Blood 107:843-844)

2004     Polymorphism in beta-2 receptor is associated with reduced response to beta-2 agonists used to treat asthma (Weiss group: Oct 2004 J Allergy Clin Immunol 114:747-754)

2004     Discovery that variations in CRHR1 affects how asthmatics respond to steroids (Weiss group: Jul 1, 2004 Hum Mol Genet 13:1353-1359)

2004     PharmGKB has 64 PK/PD genes with data; 2100 unique variants; 95 phenotype submissions

2004     A genetic variant in UGT1A1 is associated with severe neutropenia. Discovery results in FDA-mandated change in irinotecan labeling.   (Ratain group: Apr 15, 2004 J Clin Oncol 22:1382-1388)

2003-2006 Genetic variations in CYP2D6 affect endoxifen levels and clinical outcomes in those treated with tamoxifen. Ultimately, clinical guidelines are changed to disallow the use of SSRIs with tamoxifen. (Flockhart group: Dec 3, 2003 JNCI 95:1758-1764; Jan 5, 2005 JNCI 97:30-39; Dec 20, 2005 J Clin Oncol 23:9312-9318; Jul 2006 Clin Pharmacol Ther 80:61-74)

2003     SSRIs, common antidepressants, are shown to block the metabolism of tamoxifen to endoxifen by CYP2D6 (Flockhart group: Dec 3, 2003 JNCI 95:1758-1764)

2003     Pharmacogenetic studies introduced to mouse phenome project (McLeod group: Oct 2003 J Appl Physiol 95:1352-1360)

2003     Polymorphisms of beta-1 receptor are associated with lower anti-hypertensive response to beta adrenergic blocking agents (Johnson group: Jul 2003 Clin Pharmacol Ther 74:44-52)

2003     About 550 novel SNPs are discovered in 25 membrane transporter genes (Giacomini group: May 13 2003 PNAS 100:5896-5901)

2003     PharmGKB has 1000 literature annotations

2002     PharmGKB has 120 registered users and 2200 Web site visitors/month

2002     Newly identified mutations in potassium channel genes account for 5 to 10 percent of drug-induced long QT syndrome (Roden group: Apr 23 2002 Circulation 105:1943-1948)

2000     Endoxifen is identified as the active metabolite of tamoxifen (Flockhart group: Dec 3, 2003 JNCI 95:1758-1764)

2000     A potassium channel polymorphism is associated with drug-induced long QT syndrome (Roden group: Sep 12 2000 PNAS 97:10613-10618)

2000     The NIH Pharmacogenetics Research Network constructs the PharmGKB web site, the first comprehensive compilation of pharmacogenetics knowledge

2000     A draft of the human genome sequence is completed

2000     African Americans are shown to have reduced response to cholesterol-lowering statins (Krauss group: Epub Jan 27 2000 Am J Cardiol 97:843-850)

1999     Genetic variation of UGT1A1 is associated with SN38 glucuronidation and irinotecan toxicity (Ratain group: May 1999 Clin Pharmacol Ther 65:576-582)

1998     Smokers with CYP2A6 polymorphism are found to smoke less (Benowitz group: Jun 25 1998 Nature 393:750)

1997-2006 Genetic variants in a number of methyltransferases, including COMT and HNMT, are discovered and characterized (Weinshilboum group: 1996 Pharmacogenetics 6:243-250; 1998 Mol Pharmacology 53:708-717)

1997     First human organic cation and purine nucleoside transporters are cloned (Giacomini group: Jun 1997 Mol Pharmacol 51:913-921; Dec 1997 Am J Physiol 273:F1058-1065)

1995     First inactivating polymorphism identified for TPMT (Relling group: Feb 14 1995, PNAS 92:949-953)

1993-1996 TPMT gene is cloned and a variant allele is found (Weinshilboum group: 1993 Mol Pharmacology 43:878-887; 1996 Cell Biology 15:17-30)

1991     Ph

armacogenetic testing becomes standard in St. Jude acute lymphoblastic leukemia (ALL) trials (Relling group: 1999 Science 286:487-491; 2000 Leukemia 14:567-572; 2006 Blood 107:843-844)

1990s   The extent of glucuronidation of SN38 is shown to correlate with toxicity of the anticancer drug irinotecan (Ratain group: 1994 Cancer Res 54:3723-3725; 1998 J Clin Invest 101:847-854)

1987-1989 Low TPMT activity is associated with an increased risk for myelosuppression—the suppression of bone marrow activity as a side effect of cancer treatments (Weinshilboum group: 1987 Clinical Pharmacol Therapeutics 41:18-25; 1989 Clinical Pharmacol Therapeutics 46:149-154)

1980s  Clinical features of drug-induced long QT syndrome, a life-threatening form of cardiac arrhythmia, are defined (Roden group: Jun 1985 Circ Res 56:857-867; Jun 1986 Am Heart J 111:1088-1093; Jul 1986 J Am Coll Cardiol 8:73A-78A 1986)

1980     First genetic polymorphism identified in thiopurine S-methyltransferase (TPMT), a gene involved in drug metabolism (Weinshilboum group: Sep 1980 Am J Hum Genet 32:651-662)