Amish Family Diabetes Study

Walston J., Silver K., Bogardus C., Knowler W.S., Celi F.S., Austin S., Raben N., Manning B.StJ., Strosberg A.D., Sorkin J.D., Roth J., Shuldiner A.R. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic–receptor gene (1995) N. Engl. J. Med. 333, 343-347. PMID: 7609750.

Florez J.C., Jablonski K.A., Bayley N., Pollin T.I., de Bakker P.I., Shuldiner A.R., Knowler W.C., Nathan D.M., Altshuler D. for the Diabetes Prevention Program Research Group. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program (2006) N. Engl. J. Med. 355, 241-250. PMCID: PMC1762036.

Maruthur N.M., Clark J.M, Fu M., Kao L.W.H. Shuldiner A.R. Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish (2015) Diabetologia 58, 295-303. PMCID: PMC4505931

Dewey F.E., Gusarova V., O’Dushlaine C., Gottesman O., Tujos J., Hunt C., Van Hout C.V., Habegger L., Buckler D., Lai K.-M., Leader J.B., Murray M.F., Ritchie M.D., Kirchner L., Ledbetter D.H., Penn J., Lopez A., Borecki I.B., Overton J.D., Reid J.G., Carey D.J., Murphy A.J., Yancopoulos G., Baras A., Gromada J., Shuldiner A.R. Inactivating variants in ANGPTL4 and risk of coronary artery disease (2016) N. Engl. J. Med. 374, 1123-1233. PMCID: PMC4900689.

Genetics of Complex Disease

Pollin T.I., Damcott C.M., Shen H., Ott S.H., Shelton J., Horenstein R.B., Post W., McLenithan J.C., Bielak L.F., Peyser P.A., Mitchell B.D., Miller M., O’Connell J.R., Shuldiner A.R. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection (2008) Science 322, 1702-1705. PMCID: PMC2673993.

Shen H., Damcott C.M., Rampersaud E., Pollin T.I., O’Connell J.O., Horenstein R.B., McArdle P.F., Peyser P.A., Bielak L.F., Post W., Chang Y.-P. C. Ryan K.A., Miller M., Shelton J., Shuldiner A.R., Mitchell B.D. Apolipoprotein B (APOB) R3500Q is common in the Old Order Amish and is a major cause of increased low density lipoprotein cholesterol concentrations and coronary artery calcification (2010) Arch. Int. Med. 170, 1850-1855. PMCID: PMC3587042.

Albert J.S., Yerges-Armstrong L.M., Horenstein R.B., Pollin T.I., Sreenivasan U.T., Chai S., Blaner W.S., Snitker S., O'Connell J.R., D.-W., Breyer R.J. III, Ryan A.S., McLenithan J.C., Shuldiner A.R., Sztalryd C., Damcott C.M. Novel human HSL null mutation increases risk for type 2 diabetes (2014) N. Engl. J. Med. 370, 2307-2315. PMCID: PMC3942158.

Tise C.G., Perry J.A., Anforth L.E., Pavlovich M.A., Backman J.D., Ryan K.A., Lewis J.P., O’Connell J.R., Yerges-Armstrong L.M., Shuldiner A.R. From genotype to phenotype: Nonsense variants in SLC13A1 are associated with decreased serum sulfate and increased serum aminotransferases (2016) G3 (Bethesda) 2016 Sep 8;6(9):2909-18. PMCID: PMC5015947.

Pharmacogenomics

Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy (2009) JAMA. Aug 26;302(8):849-857. PMCID: PMC3641569.

Shuldiner AR, Relling MV, Peterson JF, Hicks K, Freimuth RR, Sadee W, Pereira NL, Roden DM, Johnson JA, Klein TE. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-World Implementation (2013) Clin Pharmacol Ther. Aug;94(2):207-10. PMCID: PMC3720847.

Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, Klein TE, Sabatine MS, Johnson JA, Shuldiner AR. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update (2013) Clin Pharmacol Ther. Sep;94(3):317-23. PMCID: PMC3748366.

Lewis JP, Ryan K, O'Connell JR, Horenstein RB, Damcott CM, Gibson Q, Pollin TI, Mitchell BD, Beitelshees AL, Pakzy R, Tanner K, Parsa A, Tantry US, Bliden KP, Post WS, Faraday N, Herzog W, Gong Y, Pepine CJ, Johnson JA, Gurbel PA, Shuldiner AR. Genetic Variation in PEAR1 Is Associated With Platelet Aggregation and Cardiovascular Outcomes (2013) Circ Cardiovasc Genet. Apr 1;6(2):184-192. PMCID: PMC3715320.

Dr. Shuldiner’s major research interests lie in genetics of age-related diseases, including Type 2 diabetes (T2D), obesity, and cardiovascular disease - common disorders of aging that contribute significantly to mortality, morbidity, and health care costs in the United States and world-wide. He also works on the pharmaco- and nutri-genomics of these disorders. His vision is to make genomic discoveries that lead to more effective individualized treatment and prevention of these diseases (Personalized Medicine). Dr Shuldiner is best known for his studies in the Old Order Amish, a homogeneous founder population ideal for genetic studies. He leads a large multidisciplinary research team that uses state-of-the-art molecular genetic, statistical and epidemiological methods, including both candidate gene and genome wide approaches. Dr. Shuldiner’s group was the first to identify the Pro12Ala PPARG2 variant, a common functional susceptibility allele for T2D. He is a member of the Diabetes Prevention Program’s Genetics Group, the first group to replicate and extend into a prospective study the role of variants in TCF7L2 in T2D.  More recent genome-wide association studies (GWAS) in the Amish have uncovered novel mutations that have informed human biology and population genetics.  His group identified the first APOC3null mutation in humans. Mutation carriers have low serum triglycerides, less coronary artery calcification, and are more likely to live past the age of 90 years. This genetic “proof-of-principle” experiment of nature validates apoCIII as a novel target for the treatment of hypertriglyceridemia and has provided the impetus for the initiation of apoCIII inhibitor programs at a number of pharmaceutical and biotechnology companies.  His group contributed to meta-GWAS studies of T2D, BMI, waist circumference, serum lipids, blood pressure, and other metabolic and cardiovascular traits. These studies, published in high-profile journals such as Nature, Nature Genetics, andAJHG identified more than 100 novel loci and genes for these complex traits. These loci promise to unveil new biology and potential targets for treatment and prevention of T2D and cardiovascular disease. Most recently, his group identified a common gene variant inCYP2C19 that is associated with poorer response to clopidogrel (Plavix). These findings along with candidate gene reports led to an FDA-mandated boxed warning on the package insert and recommendations for CYP2C19 genetic testing for more effective and individualized anti-platelet therapy in patients undergoing percutaneous coronary interventions and in patients with acute coronary syndromes.  His research has been supported continuously since 1995 by NIH and other competitive peer-reviewed foundation grants.

Dr. Shuldiner is strongly committed to the training of young investigators in multidisciplinary patient-oriented research in aging, endocrinology and genetics research. He was PI of the UM-NIH Roadmap K12 Multidisciplinary Clinical Scholars Program designed to support the career development of more than 20 junior faculty.  Over the years, Dr. Shuldiner has mentored 20 predoctoral students, 30 postdoctoral trainees and 32 junior faculty, most of whom have pursued successful academic careers. 

• Mallinckrodt Foundation Scholar Award, 1991-1993
• American Federation of Aging Research Award for Biomedical Research, 1993 
• 1995 Paul Beeson Physician Faculty Scholar Award, 1995
• Ellison Medical Foundation Senior Scholar Award, 2000
• Board Member, Clinical Therapeutics, 2002-2008
• Fellow, American College of Physicians, 2003
• Mary Betty Stevens Award for Excellence in Clinical Research, 2003
• Herman O. Mosenthal Memorial Award, Gerald J. Friedman Symposium of the Eastern Region of the American Diabetes Association, New York, 2005
• Founders Day Researcher of the Year, University of Maryland, Baltimore, 2005
• Star of Hope Award, Juvenile Diabetes Research Foundation, Maryland Chapter, 2012
• Wilkinson Lectureship, Vanderbilt University, 2016

Amish help UMd. researchers better treat patients

• Research Scientist, National Institute on Aging, National Institutes of Health, 1991-1992
• Assistant and Associate Professor, Johns Hopkins University School of Medicine, Division of Geriatric Medicine and Gerontology, 1990-1996